KRAS(G12D) inhibitors

Abstract

The present invention is directed to the compounds of Formula (IV) inhibitors of KRAS(G12D). The inhibitors described herein can be useful in the treatment of diseases or disorders associated with KRAS(G12D), such as Lung cancer, Pancreatic cancer, Colorectal cancer et al. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting KRAS(G12D), methods of treating diseases or disorders associated with KRAS(G12D), and methods of synthesizing these compounds.

Description

[0001] This application claims the priority and benefit of U.S. Provisional Patent Application Serial No. 63 / 550,563, filed on February 6, 2024, entitled 'KRAS(G12D) Inhibitors.' The disclosure of this provisional application is incorporated herein by reference in its entirety for all purposes. FIELD OF INVENTION

[0002] The present invention is directed to inhibitors of Kirsten rat sarcoma virus with G12D mutation - KRAS(G12D). The inhibitors described herein can be useful in the treatment of diseases or disorders associated with KRAS(G12D), such as pancreatic cancers, colorectal cancers, and lung cancers by inducing durable responses. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting KRAS(G12D), methods of treating diseases or disorders associated with KRAS(G12D), and methods of synthesizing these compounds. BACKGROUND

[0003] The oncogenic impacts of the KRAS gene were first reported in 1980s, making KRAS one of the first identified oncogenes. It is known that KRAS protein functions as a molecular switch: it responds to upstream EGFR activation and regulates the downstream MAPK and PI3K / mT0R pathways, eventually controlling cell proliferation, differentiation, and survival.

[0004] Clinical data have implicated the driver mutations of the KRAS residue Glyl2 (G12), and basic studies have shown that such mutations impair both this enzyme’s intrinsic and GTPase-activating protein (GAP)-stimulated GTP hydrolysis activity promoting oncogenesis. Despite nearly four decades of efforts, no direct KRAS inhibitor has been approved for medical use. There is consensus that the difficulty in developing direct KRAS inhibitors relates on the one hand to the picomolar affinity of GTP and GDP to KRAS (the intracellular concentrations of these metabolites are much higher), and on the other hand to an absence of suitable deep pockets for allosteric regulation.

[0005] One major breakthrough for KRAS inhibition was the discovery of an allosteric switch-II pocket (S-IIP) that is induced by covalent inhibitors of KRAS bearing the G12C driver mutation. Studies have shown that induction of S-IIP results from covalent bond formation between the electrophilic acryloyl moieties of these inhibitors and the nucleophilic thiol moiety of the Cys residue at position 12. These KRAS(G12C) inhibitors have shown promising results in recent clinical trials, although it is notable that they exclusively target KRAS in inactive state. Despite these progresses with inhibitors of KRAS(G12C), the most prevalent and oncogenic G12 mutant variant is KRAS(G12D), which is estimated to impact about 50% patients with pancreatic ductal adenocarcinoma

[0006] Pancreatic cancer is an aggressive disease that is notoriously resistant to treatment. Many cancer types and most pancreatic cancers are driven by mutations in a gene called KRAS, so researchers have long sought drugs that block the actions of mutant KRAS proteins made from these altered genes. But many efforts to develop drugs that block the cancer-fueling effects of mutant KRAS proteins have been unsuccessful.

[0007] Pancreatic cancer is the third leading cause of cancer death in the United States and often is diagnosed at a late stage, when treatment options are limited and the prognosis is poor.

[0008] Various strategies have been testified for targeting KRAS(G12D), including those using indole-based small molecules to target a switch-I / II pocket, a compound (KAL-21404358) to target the Pl 10 site, a pan-RAS inhibitor (compound 3144) to target the A59 site, and a cyclic peptide (KD2) to target KRAS(G12D). However, no one of these molecules targets KRAS(G12D) with suitably low (micromolar) concentration. A compound targeting the aspartic acid residue of KRAS(G12D) may somehow bind to KRAS(G12D) (similar to that formed between inhibitors and the cysteine residue of KRAS(G12C)), as a result may induce an allosteric pocket. This would perhaps enable pharmacological inhibition of this more prevalent oncodriver-mutation-bearing KRAS variant. However, these inhibitors are also associated with off-target effects, likely due to binding and inhibiting some non-KRAS small GTPases, which warrants further structural optimizations.

[0009] Although many studies have been done on KRAS G12D inhibitors to date, work is still underway to overcome KRAS G12D inhibitor resistance, bioavailability, efficiency and solubility those are significant problems in patients’ treatment. SUMMARY

[0010] A first aspect of the invention relates to compounds of Formula (IV): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: Q is selected from N, C-H, C-F, C-Cl, C-CHF2, and C-CF3; R1 is selected from H and halogen; R4 is selected from H, halogen and -CR9R10Rn; R3 is H, or R3 and R11 form a bond; R6 is selected from H, aryl, heterocyclyl, heteroaryl, wherein aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, Ci-Ce alkoxy; R7isH, or R6 and R7 together with the atoms to which they are attached and any intervening atoms, form a 3-8 membered cycloalkyl or heterocycle; R8 is selected from H, halogen and Ci-Ce alkyl, wherein alkyl is optionally substituted with one or more substitutients independently selected from halogen, CN, OH; R9 is selected from H and halogen; R10 is selected from H and halogen; R11 is selected from H, or R11 and R5 form a bond.

[0011] In some embodiments, the invention is directed to pharmaceutical compositions comprising a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0012] Another aspect of the invention relates to a method of treating a disease or disorder associated with KRAS(G12D). The method comprises administering to a patient in need of a treatment for diseases or disorders associated with KRAS(G12D) an effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0013] Another aspect of the invention is directed to a method of inhibiting of KRAS(G12D). The method involves administering to a patient in need thereof an effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0014] Another aspect of the present invention relates to compounds of Formula (IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting KRAS(G12D).

[0015] Another aspect of the present invention relates to the use of compounds of Formula (IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with KRAS(G12D).

[0016] Another aspect of the present invention relates to compounds of Formula (IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0017] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0018] Another aspect of the present invention relates to the use of compounds of Formula (IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0019] The present invention further provides methods of treating a disease or disorder associated with KRAS(G12D), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0020] The present invention provides inhibitors of KRAS(G12D) that are therapeutic agents in the treatment of diseases and disorders.

[0021] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known inhibitors of KRAS(G12D). The present disclosure also provides agents with novel mechanisms of action toward KRAS(G12D) in the treatment of various types of diseases.

[0022] The present invention further provides methods of treating Cancer diseases, Endocrine diseases, Genetic diseases, Neuronal diseases, Respiratory diseases, Gastrointestinal diseases, Rare diseases, Metabolic diseases, Blood diseases, Immune diseases, Reproductive diseases, Skin diseases, Bone diseases, Cardiovascular diseases, Ear diseases, Eye diseases, Fetal diseases, Mental diseases, Nephrological diseases, Liver diseases, Bone diseases, Muscle diseases, Oral diseases comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0023] The present invention further provides methods of treating a disease, disorder, or condition selected from: Lung Cancer (LNCR); Pancreatic Cancer (PNCA); Colorectal Cancer (CRC); Adenocarcinoma; Gastric Cancer (GASC); Breast Cancer (BC); Noonan Syndrome 1 (NS1); Lung Cancer Susceptibility 3 (LNCR3); Ovarian Cancer (OC); Juvenile Myelomonocytic Leukemia (JMML); Leukemia, Acute Myeloid (AML); Cardiofaciocutaneous Syndrome 1 (CFC1); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Myeloma, Multiple (MM); Leukemia, Chronic Myeloid (CML); Lynch Syndrome (HNPCC); Hepatocellular Carcinoma (HCC); Melanoma; Prostate Cancer (PC); Esophageal Cancer (ESCR); Familial Adenomatous Polyposis (FAP); Costello Syndrome (CSTLO); Skin Melanoma; Gastrointestinal Stromal Tumor (GIST); Tatton-Brown-Rahman Syndrome (TBRS); Mismatch Repair Cancer Syndrome 1 (MMRCS1); Glioma Susceptibility 1 (GLM1); Retinoblastoma (RBI); Brain Cancer; Squamous Cell Carcinoma, Head and Neck (HNSCC); Down Syndrome; Tuberous Sclerosis 1 (TSC1); Deficiency Anemia; Multiple Endocrine Neoplasia, Type I (MEN1); Medulloblastoma (MDB); Hypertension, Essential (EHT); Fanconi Anemia, Complementation Group a (FANCA); Type 2 Diabetes Mellitus (T2D); Amyotrophic Lateral Sclerosis 1 (ALS1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0024] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedure).

[0025] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.

[0026] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure.

[0027] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure, comprising one or more steps described herein.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0029] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION

[0030] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder associated with the KRAS(G12D) by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein.

[0031] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Definitions

[0032] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0033] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0034] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g, an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -C00H, -CH2CN, -O-(Ci-C6) alkyl, (Ci-C6) alkyl, (Ci-C6) alkoxy, (Ci-C6) haloalkyl, (Ci-Cs) haloalkoxy, -0-(C2-Ce) alkenyl, -0-(C2-Ce) alkynyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C6) alkyl, -C(O)(Ci-C6) alkyl, -OC(O)O(C1-C6) alkyl, -NH2, -NH((Ci-C6) alkyl), -N((Ci-C6) alkyl)2, -NHC(O)(Ci-C6) alkyl, -C(O)NH(Ci-C6) alkyl, -S(O)2(Ci-C6) alkyl, -S(O)NH(Ci-C6)alkyl, and -S(O)N((Ci-C6)alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0035] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0036] As used herein, the term “unsubstituted” means that the specified group bears no substituents.

[0037] Unless otherwise specifically defined, the term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(Ci-C6)alkyl, (Ci-Cejalkyl, -O-(C2-C6)alkenyl, -O-(C2-C6) alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C6)alkyl, -C(O)(Ci-C6) alkyl, -OC(O)O(Ci-C6)alkyl, -NH2, -NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -S(O)2-(Ci-C6) alkyl, -S(O)NH(Ci-C6)alkyl, and -S(O)N((Ci-Ce)alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0038] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. A polycyclic aromatic radical includes two or more fused rings and may further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like. Unless otherwise specifically defined, “fused” means two rings sharing two ring atoms. Unless otherwise specifically defined, “spiro-fused” means two rings sharing one ring atom. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, 0, S, P, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][l,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l,2-a]pyrimidinyl, tetrahydro pyrrolo[l,2-a]pyrimidinyl, 3,4-dihydro-2H-l-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, lH-pyrido[3,4-b][l,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2- b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo [l,2,3]triazolyl, imidazo[l,2-a]pyrimidinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c] [ 1,2,5]oxadiazole, 1,3 -dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo [l,5-b][l,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with one or more fully unsaturated aromatic ring. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Furthermore, when containing three or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring spiro-fused. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, l,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, l,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizine, pyrazolo[l,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[l,2-a]indol-1 (2H)-onyl, benzo[c] [ 1,2]oxaborol-1 (3 / 7)-olyl,      6,6a,7,8-tetrahydro-9 / 7- pyrido[2,3-Z>]puyrrolo[l,2-d][l,4]oxazin-9-onyl, 1,3-benzodioxole, or 6a’,7’-dihydro-6’H,9’H-spiro[cyclopropane-l,8’-pyrido[2,3-Z>]pyrrolo[l,2-d][l,4]oxazin]-9’-onyl.

[0039] Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

[0040] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (Ci-Ce) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, Ao-propyl, Ao-butyl, sec-butyl, Ze / 7-butyl, zso-pentyl, neo-pentyl, and Ao-hexyl.

[0041] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, / ert-butoxy, or pentoxy groups.

[0042] “Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, Ao-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl, as herein defined, may be straight or branched.

[0043] “Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, Ao-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted.

[0044] The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a Ci-Ce alkylene. An alkylene may further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0045] “Cycloalkyl” means mono or polycyclic saturated carbon rings containing 3-18 carbon atoms. Polycyclic cycloalkyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkyl. A polycyclic cycloalkyl comprises at least one non-aromatic ring. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-lH-indenyl, spiro[3.5]nonyl, spiro [5.5]undecyl, bicyclo[l.l.l]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0046] “Heterocyclyl”, “heterocycle” or “heterocycloalkyl” mono or polycyclic rings containing 3-24 atoms which include carbon and one or more heteroatoms selected from N, O, S, P, or B and wherein the rings are not aromatic. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[0047] The term “aromatic” means a planar ring having An + 2 electrons in a conjugated system. As used herein, “conjugated system” means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs.

[0048] The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0049] The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted with one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0050] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., ON.

[0051] “Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P). A (C3-C12) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms. One or more of the carbon atoms can be substituted with a heteroatom.

[0052] The term “spiroheterocycloalkyl”, “spiroheterocycle”, or “spiroheterocyclyl” is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0053] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0054] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (IV) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0055] The present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with 2H and 14C). Deuterated (i.e., 2H or D) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

[0056] The disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, e.g., watersoluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p- toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0057] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.

[0058] An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.

[0059] The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0060] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

[0061] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0062] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0063] The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound

[0064] The term “salt’ refers to pharmaceutically acceptable salts

[0065] The term “pharmaceutically acceptable salt” also refers to a salt of the compositions of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.

[0066] “KRAS(G12D) inhibitor” as used herein refer to compounds of Formula (IV) and / or compositions comprising a compound of Formula (IV) which inhibits KRAS(G12D).

[0067] The amount of compound of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g. compounds or compositions of Formula (IV) and / or additional agents described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A “pharmacologically effective amount”, “pharmacologically effective dose”, “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a subject suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the subject reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized. Compounds of the Present Disclosure

[0068] In one aspect, the present disclosure provides compounds of Formula (IV) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: wherein Q, R1, R2, and R3 are as described herein.

[0069] It is understood that, for a compound of Formula (IV), Q, R1, R2, and R3 can each be, where applicable, selected from the groups described herein, and any group described herein for any Q, R1, R2, and R3 can be combined, where applicable, with any group described herein for one or more of the remainders of Q, R1, R2, and R3.

[0070] In some embodiments, the compounds of Formula (IV) have the structure of Formula (IV*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Q, R1, R2, and R3 are as described herein.

[0071] It is understood that, for a compound of Formula (IV*), Q, R1, R2, and R3 can each be, where applicable, selected from the groups described herein, and any group described herein for any Q, R1, R2, and R3 can be combined, where applicable, with any group described herein for one or more of the remainders of Q, R1, R2, and R3.

[0072] In some embodiments, the compounds of Formula (IV) have the structure of Formula (IV**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Q, R1, R2, and R3 are as described herein.

[0073] It is understood that, for a compound of Formula (IV**), Q, R1, R2, and R3 can each be, where applicable, selected from the groups described herein, and any group described herein for any Q, R1, R2, and R3 can be combined, where applicable, with any group described herein for one or more of the remainders of Q, R1, R2, and R3.

[0074] In some embodiments, the compound is of Formula (IV-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0075] In some embodiments, the compound is of Formula (IV-A*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0076] In some embodiments, the compound is of Formula (IV-A**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0077] In some embodiments, the compound is of Formula (IV-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0078] In some embodiments, the compound is of Formula (IV-B*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0079] In some embodiments, the compound is of Formula (IV-B**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0080] In some embodiments, the compound is of Formula (IV-C): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0081] In some embodiments, the compound is of Formula (IV-C*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0082] In some embodiments, the compound is of Formula (IV-C**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0083] In some embodiments, the compound is of Formula (IV-D): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0084] In some embodiments, the compound is of Formula (IV-D*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0085] In some embodiments, the compound is of Formula (IV-D**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0086] In some embodiments, the compound is of Formula (IV-A-1): (IV-A-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0087] In some embodiments, the compound is of Formula (IV-A-1*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0088] In some embodiments, the compound is of Formula (FV-A-1**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0089] In some embodiments, the compound is of Formula (FV-A*-1): (IV-A*-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0090] In some embodiments, the compound is of Formula (IV-A*-1*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0091] In some embodiments, the compound is of Formula (FV-A*-1**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0092] In some embodiments, the compound is of Formula (IV-A**-1): (IV-A**-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0093] In some embodiments, the compound is of Formula (IV-A**-1*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0094] In some embodiments, the compound is of Formula (FV-A**-!**): (IV-A**-1**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0095] In some embodiments, the compound is of Formula (IV-B-1): (IV-B-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0096] In some embodiments, the compound is of Formula (IV-B-1*): (IV-B-1*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0097] In some embodiments, the compound is of Formula (IV-B-1**): (IV-B-1**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0098] In some embodiments, the compound is of Formula (IV-BM): (IV-BM), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0099] In some embodiments, the compound is of Formula (IV-BM*): (IV-BM*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0100] In some embodiments, the compound is of Formula (IV-BM**): (IV-BM**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0101] In some embodiments, the compound is of Formula (IV-B**-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0102] In some embodiments, the compound is of Formula (IV-B**-1*): (FV-B**-!*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0103] In some embodiments, the compound is of Formula (FV-B**-1**): (FV-B**-1**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0104] In some embodiments, the compound is of Formula (IV-C-1): (IV-C-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0105] In some embodiments, the compound is of Formula (IV-C-1*): (IV-C-1*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0106] In some embodiments, the compound is of Formula (IV-C-1**): (IV-C-1**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0107] In some embodiments, the compound is of Formula (FV-C*-1): (IV-C*-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0108] In some embodiments, the compound is of Formula (IV-CM*): (IV-C*-1*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0109] In some embodiments, the compound is of Formula (FV-CM**): (IV-CM**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0110] In some embodiments, the compound is of Formula (IV-C**-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0111] In some embodiments, the compound is of Formula (IV-C**-1*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0112] In some embodiments, the compound is of Formula (IV-C**-1**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0113] In some embodiments, the compound is of Formula (IV-D-1): (IV-D-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0114] In some embodiments, the compound is of Formula (IV-D-1*): (IV-D-1*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0115] In some embodiments, the compound is of Formula (IV-D-1**): (IV-D-1**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0116] In some embodiments, the compound is of Formula (FV-D*-1): (IV-D*-1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0117] In some embodiments, the compound is of Formula (IV-D*-1*): (IV-DM*), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0118] In some embodiments, the compound is of Formula (FV-D*-!**): (IV-D*-1**), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0119] In some embodiments, the compound is of Formula (IV-D**-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0120] In some embodiments, the compound is of Formula (IV-D**-1*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0121] In some embodiments, the compound is of Formula (FV-D**-1**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0122] In some embodiments, the compound is of Formula (IV-A-l-a): H N R1 OH (IV-A-l-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0123] In some embodiments, the compound is of Formula (FV-A-l*-a): OH (IV-A-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0124] In some embodiments, the compound is of Formula (IV-A-l**-a): (IV-A-l**-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0125] In some embodiments, the compound is of Formula (IV-A*-l-a): (IV-A*-l-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0126] In some embodiments, the compound is of Formula (IV-A*-l*-a): (FV-A*-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0127] In some embodiments, the compound is of Formula (FV-A*-l**-a): H N R OH (IV-A*-l**-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0128] In some embodiments, the compound is of Formula (FV-A**-l-a): H N R1 OH (FV-A**-l-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0129] In some embodiments, the compound is of Formula (IV-A**-l*-a): OH (FV-A**-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0130] In some embodiments, the compound is of Formula (FV-A**-l**-a): OH (IV-A**-l**-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0131] In some embodiments, the compound is of Formula (IV-B-l-a): OH (IV-B-l-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0132] In some embodiments, the compound is of Formula (IV-B-l*-a): OH (IV-B-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0133] In some embodiments, the compound is of Formula (IV-B-l**-a): H N R1 OH (FV-B-l**-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0134] In some embodiments, the compound is of Formula (IV-B*-l-a): H N R1 OH (IV-B*-l-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0135] In some embodiments, the compound is of Formula (IV-B*-l*-a): OH (FV-B*-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0136] In some embodiments, the compound is of Formula (IV-B*-l**-a): OH (FV-B*-l**-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0137] In some embodiments, the compound is of Formula (IV-B**-l-a): OH (IV-B**-l-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0138] In some embodiments, the compound is of Formula (IV-B**-l*-a): OH (IV-B**-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0139] In some embodiments, the compound is of Formula (IV-B**-l**-a): OH or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0140] In some embodiments, the compound is of Formula (IV-C-l-a): OH (IV-C-l-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0141] In some embodiments, the compound is of Formula (IV-C-l*-a): OH (IV-C-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0142] In some embodiments, the compound is of Formula (FV-C-l**-a): OH (IV-C-l**-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0143] In some embodiments, the compound is of Formula (IV-C*-l-a): OH (IV-C*-l-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0144] In some embodiments, the compound is of Formula (FV-C*-l*-a): OH (IV-C*-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0145] In some embodiments, the compound is of Formula (IV-C*-l**-a): OH (FV-C*-l**-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0146] In some embodiments, the compound is of Formula (FV-C**-l-a): OH (IV-C**-l-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0147] In some embodiments, the compound is of Formula (IV-C**-l*-a): OH (FV-C**-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0148] In some embodiments, the compound is of Formula (IV-C**-l**-a): OH (IV-C**-l**-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0149] In some embodiments, the compound is of Formula (IV-D-l-a): OH (IV-D-l-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0150] In some embodiments, the compound is of Formula (IV-D-l*-a): OH (IV-D-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0151] In some embodiments, the compound is of Formula (IV-D-l**-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0152] In some embodiments, the compound is of Formula (IV-D*-l-a): OH (IV-D*-l-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0153] In some embodiments, the compound is of Formula (IV-D*-l*-a): F H N R1 OH (IV-D*-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0154] In some embodiments, the compound is of Formula (FV-D*-l**-a): H OH (IV-D*-l**-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0155] In some embodiments, the compound is of Formula (IV-D**-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0156] In some embodiments, the compound is of Formula (IV-D**-l*-a): OH (IV-D**-l*-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0157] In some embodiments, the compound is of Formula (FV-D**-l**-a): OH (IV-D**-1 **-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0158] In some embodiments, the compound is of Formula (IV-A-l-b): (IV-A-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0159] In some embodiments, the compound is of Formula (lV-A-l*-b): (IV-A-l*-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0160] In some embodiments, the compound is of Formula (FV-A-l**-b): NH2 (IV-A-l**-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0161] In some embodiments, the compound is of Formula (IV-A*-l-b): (TV-A*-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0162] In some embodiments, the compound is of Formula (FV-A*-l*-b): (IV-A*-l*-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0163] In some embodiments, the compound is of Formula (IV-A*-l**-b): NH2 (IV-A*-l**-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0164] In some embodiments, the compound is of Formula (IV-A**-l-b): NH2 (IV-A**-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0165] In some embodiments, the compound is of Formula (TV-A**-l*-b): (IV-A**-l*-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0166] In some embodiments, the compound is of Formula (FV-A**-l**-b): (IV-A**-l**-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0167] In some embodiments, the compound is of Formula (IV-B-l-b): (IV-B-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0168] In some embodiments, the compound is of Formula (IV-B-l*-b): (IV-B-l*-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0169] In some embodiments, the compound is of Formula (FV-B-l**-b): (IV-B-l**-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0170] In some embodiments, the compound is of Formula (TV-BM-b): (IV-B*-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0171] In some embodiments, the compound is of Formula (TV-B*-l*-b): NH2 (IV-B*-l*-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0172] In some embodiments, the compound is of Formula (FV-B*-l**-b): NH2 (IV-B*-l**-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0173] In some embodiments, the compound is of Formula (FV-B**-l-b): (IV-B**-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0174] In some embodiments, the compound is of Formula (FV-B**-l*-b): (IV-B**-l*-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0175] In some embodiments, the compound is of Formula (IV-B**-l**-b): NH2 or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0176] In some embodiments, the compound is of Formula (IV-C-l-b): NH2 (IV-C-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0177] In some embodiments, the compound is of Formula (IV-C-l*-b): (IV-C-l*-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0178] In some embodiments, the compound is of Formula (FV-C-l**-b): (IV-C-l**-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0179] In some embodiments, the compound is of Formula (IV-C*-l-b): NH2 (IV-C*-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0180] In some embodiments, the compound is of Formula (FV-C*-l*-b): NH2 (IV-C*-l*-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0181] In some embodiments, the compound is of Formula (IV-C*-l**-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0182] In some embodiments, the compound is of Formula (FV-C**-l-b): (IV-C**-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0183] In some embodiments, the compound is of Formula (IV-C**-l*-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0184] In some embodiments, the compound is of Formula (IV-C**-l**-b): (TV-C**-l**-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0185] In some embodiments, the compound is of Formula (IV-D-l-b): (IV-D-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0186] In some embodiments, the compound is of Formula (FV-D-l*-b): (IV-D-l*-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0187] In some embodiments, the compound is of Formula (IV-D-l**-b): (IV-D-l**-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0188] In some embodiments, the compound is of Formula (IV-D*-l-b): (IV-D*-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0189] In some embodiments, the compound is of Formula (IV-D*-l*-b): NH2 (IV-D*-l*-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0190] In some embodiments, the compound is of Formula (FV-D*-l**-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0191] In some embodiments, the compound is of Formula (IV-D**-l-b): (IV-D**-l-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0192] In some embodiments, the compound is of Formula (FV-D**-l*-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0193] In some embodiments, the compound is of Formula (TV-D**-l**-b): (IV-D**-l**-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R4 is selected from H, F, CH3, and R1 is as described herein.

[0194] In some embodiments, the compound is of Formula (IV-A-l-c): (IV-A-l-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0195] In some embodiments, the compound is of Formula (IV-A-l*-c): (IV-A-l*-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0196] In some embodiments, the compound is of Formula (IV-A-l**-c): (IV-A-l**-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0197] In some embodiments, the compound is of Formula (IV-A*-l-c): (IV-A*-l-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0198] In some embodiments, the compound is of Formula (IV-A*-l*-c): (IV-A*-l*-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0199] In some embodiments, the compound is of Formula (FV-A*-l**-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0200] In some embodiments, the compound is of Formula (IV-A**-l-c): (IV-A**-l-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0201] In some embodiments, the compound is of Formula (IV-A**-l*-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0202] In some embodiments, the compound is of Formula (FV-A**-l**-c): (IV-A**-l**-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0203] In some embodiments, the compound is of Formula (IV-B-l-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0204] In some embodiments, the compound is of Formula (FV-B-l*-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0205] In some embodiments, the compound is of Formula (FV-B-l**-c): H R7 (IV-B-l**-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0206] In some embodiments, the compound is of Formula (FV-BM-c): R7 (IV-B*-l-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0207] In some embodiments, the compound is of Formula (FV-B*-l*-c): R7 (IV-B*-l*-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0208] In some embodiments, the compound is of Formula (IV-B*-l**-c): R7 (IV-B*-l**-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0209] In some embodiments, the compound is of Formula (IV-B**-l-c): R7 (IV-B**-l-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0210] In some embodiments, the compound is of Formula (IV-B**-l*-c): R7 (IV-B**-l*-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0211] In some embodiments, the compound is of Formula (IV-B**-l**-c): R7 (FV-B**-l**-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0212] In some embodiments, the compound is of Formula (IV-C-l-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0213] In some embodiments, the compound is of Formula (IV-C-l*-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0214] In some embodiments, the compound is of Formula (IV-C-l**-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0215] In some embodiments, the compound is of Formula (FV-CM-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0216] In some embodiments, the compound is of Formula (FV-C*-l*-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0217] In some embodiments, the compound is of Formula (IV-C*-l**-c): R7 (IV-C*-l**-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0218] In some embodiments, the compound is of Formula (IV-C**-l-c): R7 (IV-C**-l-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0219] In some embodiments, the compound is of Formula (IV-C**-l*-c): R7 (IV-C**-l*-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0220] In some embodiments, the compound is of Formula (IV-C**-l**-c): R7 (IV-C**-l**-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0221] In some embodiments, the compound is of Formula (IV-D-l-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0222] In some embodiments, the compound is of Formula (FV-D-l*-c): H R7 (IV-D-l*-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0223] In some embodiments, the compound is of Formula (IV-D-l**-c): H R7 (IV-D-l**-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0224] In some embodiments, the compound is of Formula (FV-D*-l-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0225] In some embodiments, the compound is of Formula (IV-D*-l*-c): R7 (IV-D*-l*-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0226] In some embodiments, the compound is of Formula (FV-D*-l**-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0227] In some embodiments, the compound is of Formula (IV-D**-l-c): R7 (IV-D**-l-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0228] In some embodiments, the compound is of Formula (IV-D**-l*-c): H R7 (IV-D**-l*-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0229] In some embodiments, the compound is of Formula (FV-D**-l**-c): R7 (IV-D**-l**-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R5 is selected from H and -CN; R6 is selected from H, F, -CH3, -CHF2; R7 is selected from H and CH3; and R1 is as described herein.

[0230] In some embodiments, the compound is of Formula (IV-A-l-d): (IV-A-l-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0231] In some embodiments, the compound is of Formula (FV-A-l*-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0232] In some embodiments, the compound is of Formula (IV-A-l**-d): (IV-A-l**-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0233] In some embodiments, the compound is of Formula (IV-A*-l-d): (IV-A*-l-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0234] In some embodiments, the compound is of Formula (IV-A*-l*-d): (FV-A*-l*-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0235] In some embodiments, the compound is of Formula (IV-A*-l**-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0236] In some embodiments, the compound is of Formula (IV-A**-l-d): (IV-A**-l-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0237] In some embodiments, the compound is of Formula (IV-A**-l*-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Xis selected from N and C-CN; andR1 is as described herein.

[0238] In some embodiments, the compound is of Formula (FV-A**-l**-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0239] In some embodiments, the compound is of Formula (IV-B-l-d): (IV-B-l-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0240] In some embodiments, the compound is of Formula (IV-B-l*-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0241] In some embodiments, the compound is of Formula (IV-B-l**-d): F (IV-B-l**-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0242] In some embodiments, the compound is of Formula (IV-B*-l-d): (IV-B*-l-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0243] In some embodiments, the compound is of Formula (IV-B*-l*-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0244] In some embodiments, the compound is of Formula (FV-B*-l**-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0245] In some embodiments, the compound is of Formula (IV-B**-l-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Xis selected from N and C-CN; andR1 is as described herein.

[0246] In some embodiments, the compound is of Formula (FV-B**-l*-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0247] In some embodiments, the compound is of Formula (IV-B**-l**-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0248] In some embodiments, the compound is of Formula (IV-C-l-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0249] In some embodiments, the compound is of Formula (IV-C-l*-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0250] In some embodiments, the compound is of Formula (IV-C-l**-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0251] In some embodiments, the compound is of Formula (IV-C*-l-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0252] In some embodiments, the compound is of Formula (FV-C*-l*-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0253] In some embodiments, the compound is of Formula (IV-C*-l**-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Xis selected from N and C-CN; andR1 is as described herein.

[0254] In some embodiments, the compound is of Formula (FV-C**-l-d): (FV-C**-l-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0255] In some embodiments, the compound is of Formula (IV-C**-l*-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0256] In some embodiments, the compound is of Formula (IV-C**-l**-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0257] In some embodiments, the compound is of Formula (IV-D-l-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0258] In some embodiments, the compound is of Formula (IV-D-l*-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0259] In some embodiments, the compound is of Formula (IV-D-l**-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0260] In some embodiments, the compound is of Formula (IV-D*-l-d): (IV-D*-l-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0261] In some embodiments, the compound is of Formula (IV-D*-l*-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Xis selected from N and C-CN; andR1 is as described herein.

[0262] In some embodiments, the compound is of Formula (FV-D*-l**-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0263] In some embodiments, the compound is of Formula (IV-D**-l-d): (FV-D**-l-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0264] In some embodiments, the compound is of Formula (FV-D**-l*-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0265] In some embodiments, the compound is of Formula (IV-D**-l**-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein X is selected from N and C-CN; and R1 is as described herein.

[0266] In some embodiments, the compound is of Formula (IV-A-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0267] In some embodiments, the compound is of Formula (IV-A*-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0268] In some embodiments, the compound is of Formula (IV-A**-2): (IV-A**-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0269] In some embodiments, the compound is of Formula (IV-B-2): (IV-B-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0270] In some embodiments, the compound is of Formula (IV-B*-2): (IV-B*-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0271] In some embodiments, the compound is of Formula (IV-B**-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0272] In some embodiments, the compound is of Formula (IV-C-2): (IV-C-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0273] In some embodiments, the compound is of Formula (IV-C*-2): (IV-C*-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0274] In some embodiments, the compound is of Formula (IV-C**-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0275] In some embodiments, the compound is of Formula (IV-D-2): (IV-D-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0276] In some embodiments, the compound is of Formula (IV-D*-2): (FV-D*-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0277] In some embodiments, the compound is of Formula (IV-D**-2): (IV-D**-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein Y is selected from CH2, C=CH2, C=CHF, and C=CF2; and all other variables are as defined herein.

[0278] In some embodiments, the compound is of Formula (IV-A-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0279] In some embodiments, the compound is of Formula (FV-A*-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0280] In some embodiments, the compound is of Formula (IV-A**-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0281] In some embodiments, the compound is of Formula (IV-B-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0282] In some embodiments, the compound is of Formula (FV-B*-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0283] In some embodiments, the compound is of Formula (FV-B**-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0284] In some embodiments, the compound is of Formula (IV-C-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0285] In some embodiments, the compound is of Formula (IV-C*-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0286] In some embodiments, the compound is of Formula (FV-C**-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0287] In some embodiments, the compound is of Formula (IV-D-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0288] In some embodiments, the compound is of Formula (FV-D*-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0289] In some embodiments, the compound is of Formula (FV-D**-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R8 is selected from H and F; and all other variables are as defined herein.

[0290] In some embodiments, the compound is of Formula (IV).

[0291] In some embodiments, the compound is of Formula (IV-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0292] In some embodiments, the compound is of Formula (IV-B), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0293] In some embodiments, the compound is of Formula (IV-C), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0294] In some embodiments, the compound is of Formula (IV-D), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0295] In some embodiments, the compound is of Formula (IV-1): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0296] In some embodiments, the compound is of Formula (IV-l-A): (IV-1-A), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0297] In some embodiments, the compound is of Formula (IV-l-A-a): (IV-l-A-a), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0298] In some embodiments, the compound is of Formula (IV-l-A-b): (IV-l-A-b), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0299] In some embodiments, the compound is of Formula (IV-l-A-c): (IV-l-A-c), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0300] In some embodiments, the compound is of Formula (IV-l-A-d): (IV-l-A-d), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0301] In some embodiments, the compound is of Formula (IV-l-A-e): (IV-l-A-e), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0302] In some embodiments, the compound is of Formula (IV-l-A-f): (IV-l-A-f), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0303] In some embodiments, the compound is of Formula (IV-2): (IV-2), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0304] In some embodiments, the compound is of Formula (IV-2-A): (IV-2-A), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0305] In some embodiments, the compound is of Formula (IV-2-A-a): (IV-2-A-a), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0306] In some embodiments, the compound is of Formula (IV-2-A-b): (IV-2-A-b), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0307] In some embodiments, the compound is of Formula (IV-2-A-c): (IV-2-A-c), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0308] In some embodiments, the compound is of Formula (IV-2-A-d): (IV-2-A-d), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0309] In some embodiments, the compound is of Formula (IV-2-A-e): (IV-2-A-e), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0310] In some embodiments, the compound is of Formula (IV-2-A-f): (IV-2-A-f), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0311] In some embodiments, the compound is of Formula (TV-3): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0312] In some embodiments, the compound is of Formula (1V-3-A): (IV-3-A), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0313] In some embodiments, the compound is of Formula (IV-3-A-a): (IV-3-A-a), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0314] In some embodiments, the compound is of Formula (IV-3-A-b): (IV-3-A-b), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0315] In some embodiments, the compound is of Formula (IV-3-A-c): (IV-3-A-c), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0316] In some embodiments, the compound is of Formula (IV-3-A-d): (IV-3-A-d), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0317] In some embodiments, the compound is of Formula (IV-3-A-e): (IV-3-A-e), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0318] In some embodiments, the compound is of Formula (FV-3-A-f): (IV-3-A-f), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0319] In some embodiments, the compound is of Formula (IV-4): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0320] In some embodiments, the compound is of Formula (IV-4-A): (IV-4-A), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0321] In some embodiments, the compound is of Formula (IV-4-A-a): (IV-4-A-a), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0322] In some embodiments, the compound is of Formula (IV-4-A-b): (IV-4-A-b), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0323] In some embodiments, the compound is of Formula (FV-4-A-c): (IV-4-A-c), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0324] In some embodiments, the compound is of Formula (IV-4-A-d): (IV-4-A-d), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0325] In some embodiments, the compound is of Formula (IV-4-A-e): (IV-4-A-e), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0326] In some embodiments, the compound is of Formula (IV-4-A-f): (IV-4-A-f), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0327] In some embodiments, the compound is of Formula (TV-5): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0328] In some embodiments, the compound is of Formula (IV-5-A): (IV-5-A), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0329] In some embodiments, the compound is of Formula (IV-5-A-a): (IV-5-A-a), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0330] In some embodiments, the compound is of Formula (IV-5-A-b): (IV-5-A-b), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0331] In some embodiments, the compound is of Formula (IV-5-A-c): (IV-5-A-c), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0332] In some embodiments, the compound is of Formula (IV-5-A-d): (IV-5-A-d), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0333] In some embodiments, the compound is of Formula (IV-5-A-e): (IV-5-A-e), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0334] In some embodiments, the compound is of Formula (IV-5-A-f): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0335] In some embodiments, the compound is of Formula (IV-6): (IV-6), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0336] In some embodiments, the compound is of Formula (IV-6-A): (IV-6-A), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0337] In some embodiments, the compound is of Formula (IV-6-A-a): (IV-6-A-a), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0338] In some embodiments, the compound is of Formula (IV-6-A-b): (IV-6-A-b), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0339] In some embodiments, the compound is of Formula (IV-6-A-c): (IV-6-A-c), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0340] In some embodiments, the compound is of Formula (IV-6-A-d): (IV-6-A-d), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0341] In some embodiments, the compound is of Formula (IV-6-A-e): (IV-6-A-e), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0342] In some embodiments, the compound is of Formula (IV-6-A-f): (IV-6-A-f), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0343] In some embodiments, the compound is of Formula (IV-7): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0344] In some embodiments, the compound is of Formula (IV-7-A): (IV-7-A), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0345] In some embodiments, the compound is of Formula (IV-7-A-a): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0346] In some embodiments, the compound is of Formula (IV-7-A-b): (IV-7-A-b), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0347] In some embodiments, the compound is of Formula (IV-7-A-c): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0348] In some embodiments, the compound is of Formula (IV-7-A-d): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0349] In some embodiments, the compound is of Formula (IV-7-A-e): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0350] In some embodiments, the compound is of Formula (IV-7-A-f): (IV-7-A-f), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0351] In some embodiments, the compound is of Formula (IV-8): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0352] In some embodiments, the compound is of Formula (IV-8-A): (IV-8-A), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0353] In some embodiments, the compound is of Formula (IV-8-A-a): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0354] In some embodiments, the compound is of Formula (IV-8-A-b): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0355] In some embodiments, the compound is of Formula (IV-8-A-c): (IV-8-A-c), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0356] In some embodiments, the compound is of Formula (IV-8-A-d): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0357] In some embodiments, the compound is of Formula (IV-8-A-e): (IV-8-A-e), or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0358] In some embodiments, the compound is of Formula (IV-8-A-f): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

[0359] In some embodiments, Q is selected from N, C-H, C-F, C-Cl, and C-CF3.

[0360] In some embodiments, Q is CH.

[0361] In some embodiments, Q is N.

[0362] In some embodiments, Q is C-F.

[0363] In some embodiments, Q is C-Cl.

[0364] In some embodiments, Q is C-CHF2.

[0365] In some embodiments, Q is C-CF3.

[0366] In some embodiments, R1 is selected from H and halogen.

[0367] In some embodiments, R1 is H.

[0368] In some embodiments, R1 is halogen.

[0369] In some embodiments, R1 is F.

[0370] In some embodiments, R1 is Cl.

[0371] In some embodiments, R1 is Br.

[0372] In some embodiments, R1 is I. In some embodiments, R2 is

[0379] In some embodiments, R2 is

[0380] In some embodiments, R2 is

[0381] In some embodiments, R2 is

[0382] In some embodiments, R2 is

[0383] In some embodiments, R2 is

[0384] In some embodiments, R2 is

[0385] In some embodiments, R2 is

[0386] In some embodiments, R2 is

[0387] In some embodiments, R2 is F

[0388] In some embodiments, R2 is

[0389] In some embodiments, R2 is

[0390] In some embodiments, R2 is F

[0391] In some embodiments, R2 is

[0394] In some embodiments, R2 is

[0397] In some embodiments, R2 is

[0398] In some embodiments, R2 is

[0399] In some embodiments, R2 is

[0400] In some embodiments, R2 is

[0401] In some embodiments, R2 is

[0402] In some embodiments, R2 is

[0403] In some embodiments, R2 is

[0404] In some embodiments, R2 is OH

[0406] In some embodiments, R3 is F OH

[0407] In some embodiments, R3 is F

[0408] In some embodiments, R3 is NH2

[0409] In some embodiments, R3 is NH2

[0410] In some embodiments, R3 is

[0411] In some embodiments, R3 is NH2

[0412] In some embodiments, R3 is F

[0413] In some embodiments, R3 is

[0414] In some embodiments, R3 is

[0415] In some embodiments, R3 is

[0416] In some embodiments, R3 is

[0417] In some embodiments, R3 is

[0418] In some embodiments, R3 is F NH2 NH

[0419] In some embodiments, R3 is F

[0420] In some embodiments, R3 is

[0421] In some embodiments, R4 is selected from H, halogen and -CR9Rl0R'b

[0422] In some embodiments, R4 is H.

[0423] In some embodiments, R4 is halogen.

[0424] In some embodiments, R4 is F.

[0425] In some embodiments, R4 is -CR9R10Rn.

[0426] In some embodiments, R is H, or R? and R11 form a bond.

[0427] In some embodiments, R5 is H.

[0428] In some embodiments, R4 is -CR9R10Rn, R5 and R11 form a bond.

[0429] In some embodiments, R6 is selected from H, aryl, heterocyclyl, heteroaryl, wherein aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, Ci-Ce alkoxy.

[0430] In some embodiments, R6 is H.

[0431] In some embodiments, R6 is o

[0432] In some embodiments, R6 is S xcx

[0433] In some embodiments, R6 is            O

[0434] In some embodiments, R7 is H, or R6 and R7 together with the atoms to which they are attached and any intervening atoms, form a 3-8 membered cycloalkyl or heterocycle.

[0435] In some embodiments, R7is H.

[0436] In some embodiments, R6 and R7 together with the atoms to which they are attached and any intervening atoms, form a 3-8 membered cycloalkyl or heterocycle.

[0437] In some embodiments, R6 and R7 together with the atoms to which they are attached and any intervening atoms, form a 3 membered cycloalkyl.

[0438] In some embodiments, R8 is selected from H, halogen and Ci-Ce alkyl, wherein alkyl is optionally substituted with one or more substitutients independently selected from halogen, CN, OH.

[0439] In some embodiments, R8 is H.

[0440] In some embodiments, R8 is F.

[0441] In some embodiments, R8 is Ci-Ce alkyl optionally substituted with one or more substitutients independently selected from halogen, CN, OH.

[0442] In some embodiments, R8 is -CH2F.

[0443] In some embodiments, R9 is selected from H and halogen.

[0444] In some embodiments, R9 is H.

[0445] In some embodiments, R9 is halogen.

[0446] In some embodiments, R9 is F.

[0447] In some embodiments, R10 is selected from H and halogen.

[0448] In some embodiments, R10 is H.

[0449] In some embodiments, R10 is halogen.

[0450] In some embodiments, R10 is F.

[0451] In some embodiments, R11 is selected from H, or R11 and R5 form a bond.

[0452] In some embodiments, R11 is H

[0453] In some embodiments, R11 and R5 form a bond.

[0454] In some embodiments, X is selected from N and C-CN.

[0455] In some embodiments, Xis N.

[0456] In some embodiments, Xis C-CN.

[0457] In some embodiments, Y is selected from CH2, C=CH2, C=CHF, and C=CF2.

[0458] In some embodiments, Y is CH2.

[0459] In some embodiments, Y is C=CH2.

[0460] In some embodiments, Y is C=CHF.

[0461] In some embodiments, Y is C=CF2.

[0462] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[0463] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0464] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0465] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0466] In some embodiments, the compound is selected from the compounds described in Table 1

[0467] Table 1 Certain examples of the compound of Formula IV. #                  Structure                      IUPAC Name 4-(4-(1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol IUPAC Name 4-[4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol 4-[4-[(lR,5R)-1-(2,2- di fl uorovi ny 1 )-3,8 -diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol 6-[4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine Structure IUPAC Name 6-[4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine 6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine 6-[4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine Structure IUPAC Name 4-(1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-y l)methoxy )py ri do [4,3 -d]pyrimidine 4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1 ]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2- [[(2R, 8 S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidine 4-[(lR,5R)-l-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2- [[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidine IUPAC Name 4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)pyrido[4,3-d]pyrimidine 4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)pyrido[4,3-d]pyrimidine 4-[4-[(lS,5S)-l-(2,2- di fl uorovi ny 1 )-3,8 -diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-7-fluoro-1,3 -b enzothi azol -2-ami ne IUPAC Name 4-[4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-7-fluoro-l,3-benzothiazol-2-amine 2-amino-4-(4-( 1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-y l)m eth oxy )py ri do [4,3 -d]pyrimidin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 2-amino-4-[4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile IUPAC Name 2-amino-4-[4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-7-fluoro-b enzothi ophene-3 -carbonitrile 2-amino-4-[4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]benzothiophene-3-carbonitrile 2-amino-4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]benzothiophene-3-carbonitrile 4-[4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-methyl-5-(tri fluoromethyl)-1H-indazole-3-carbonitrile IUPAC Name 19 4-[4-[(lR,5R)-1-(2,2- difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-methyl-5-(tri fluoromethyl)-1H-indazol e-3 - carb onitril e 4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]pyrido[4,3 -d]pyrimidine 4-[(lR,5R)-l-(2,2- difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]pyrido[4,3-d]pyrimidine IUPAC Name 21 4-[4-[(lS,5S)-l-(2,2- di fl uorovi ny 1 )-3,8 -diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethynyl -6-fluoro-naphthalen-2-ol 22 4-[4-[(lR,5R)-1-(2,2- difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethynyl -6-fluoro-naphthalen-2-ol 6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine # Structure IUPAC Name 24 H      zF V_Z F OoaIXV N 7                 1 J \___ /              F nh2 6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine 25 H      zF £__Z F \                     CF3 OcoAII\f N 7                  I J \ /              F nh2 6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine 26 H      zF k_Z F \                     CF3 /       JL JL JC / f C        0 N         Al N 7                        1 II \ /             F nh2 6-[4-[(lR,5R)-l-(2,2- difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine Structure IUPAC Name 4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2- [[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazoline 4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2- [[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazoline 4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)quinazoline 30 31 IUPAC Name 4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)quinazoline 4-[4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-1,3 -b enzothi azol -2-amine 4-[4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-1,3 -b enzothi azol -2-amine IUPAC Name 2-amino-4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile 2-amino-4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile 2-amino-4-[4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile 2-amino-4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile 37 38 IUPAC Name 4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrile 4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-i ndazol e-3 - carb oni tril e 4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl]quinazoline IUPAC Name 40 4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]quinazoline 4-(6-Chloro-4-(l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 4-[6-chloro-4-[( 1 S,5 S)-1 -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethy nyl -6-fluoro-naphthalen-2-ol # Structure IUPAC Name 42 H       / F k_A F F                         / Cl O J JU F^^U 4-[6-chloro-4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethy ny 1 -6-fluoro-naphthalen-2-ol 43 H      ZF U N \   nUvc /  \^x                ,NH2 w " vG 6-[6-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine 44 H       / F / NxyU^X _Z F F           / V ^Cl \       N / \^x xJL xX      _N^ ,NH2 O J JU '—'          f3c^ 6-[6-chloro-4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine IUPAC Name 6-[6-chloro-4-[( 1 S,5 S)-1 -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine 6-[6-chloro-4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine 6-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazoline Structure IUPAC Name 6-chl oro-4- [(1R, 5R)-1 -(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2-[[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazoline 49 6-chl oro-4- [(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl- lH-indazol-4-yl)quinazoline 6-chl oro-4- [(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl- lH-indazol-4-yl)quinazoline IUPAC Name 4-[6-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-1,3 -b enzothi azol -2-amine 4-[6-chloro-4-[(lR,5R)-l- (2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-1,3 -b enzothi azol -2-amine 2-amino-4- [6-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile 2-amino-4-[6-chloro-4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile # 55 56 IUPAC Name 2-amino-4- [6-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile 2-amino-4-[6-chloro-4-[(lR,5R)-l-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile 4-[6-chloro-4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrile Structure IUPAC Name 59 4-[6-chloro-4-[(lR,5R)-l- (2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrile 6-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]quinazoline 6-chloro-4- [(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]quinazoline Structure IUPAC Name 4-[4-[(lS,5S)-l-(2,2- di fl uorovi ny 1 )-3,8 -diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethynyl -6-fluoro-naphthalen-2-ol 62 4-[4-[(lR,5R)-1-(2,2- difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethynyl -6-fluoro-naphthalen-2-ol 6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine IUPAC Name 64 65 6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine 6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine 6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine # Structure IUPAC Name 67 H       / F £__Z F \   nA^F -n /      jl JL JL >C znh NO    F XJ 4-[(lS,5S)-l-(2,2- difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-6,8 -difluoro-2-[[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazoline 68 H _ zF k_Z F \ . O f AJ N-NH 4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-6,8-difluoro-2- [[(2R, 8 S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazoline 69 H      zF N _Z F \     N^y^ZF । O f JU N-NH 4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)quinazoline Structure IUPAC Name 72 4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)quinazoline 4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-1,3 -b enzothi azol -2-amine 4-[4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-1,3 -b enzothi azol -2-amine IUPAC Name 2-amino-4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile 2-amino-4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile 2-amino-4-[4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile 2-amino-4-[4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile 78 IUPAC Name 4-[4-[(lS,5S)-l-(2,2- difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazol e-3 - carb onitril e 4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluorom ethyl)-1H-i ndazol e-3 - carb onitril e 4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl]quinazoline IUPAC Name 82 4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]quinazoline 4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol 4-[4-[(lR,5R)-l-(2,2- difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol # Structure IUPAC Name 83 ^Z 1 O z     z   ZI # \ #        JI Q.      /    \       ■n'-'x \— /  o # v   n --c    z  “ z I KJ 6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine 84 <N T z u-u.     °\  M yy ° 1           #   Vl      « X      \   / - iz ] z—z y "=< o 6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine 85 H       / F _Z F F           x'L      / CF3 Sy0 N jXJ f3cx y F 6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine 86 87 Structure IUPAC Name 6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine 4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2- [[(2R, 8 S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazoline 4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2- [[(2R, 8 S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazoline Structure IUPAC Name 4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-6-(trifluoromethyl)quinazoline 90 4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-6-(trifluoromethyl)quinazoline 4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-7-flu°r°-l,3-b enzothi azol -2 -ami ne IUPAC Name 4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1 ]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-7-fluoro-l,3-benzothiazol-2-amine 2-amino-4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-7-fluoro-b enzothi ophene-3 -carbonitrile 2-amino-4-[4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile IUPAC Name 2-amino-4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7 -y 1 ] b enzothi ophene-3 -carbonitrile 2-amino-4-[4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7 -y 1 ]b enzothi ophene-3 -carbonitrile 4-[4-[(lS,5S)-l-(2,2- difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrile IUPAC Name 4-[4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrile 4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl]-6-(trifluoromethyl)quinazoline 4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluorom ethyl)- 1H-indazol-4-yl]-6-(trifluoromethyl)quinazoline IUPAC Name 4-(2-(((S)-2- (Difluoromethylene)tetrahyd ro-1 H-pyrrolizin-7 a(5H)-yl)methoxy)-4-( 1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthal en -2-ol 4-(2-(((S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy )-4-(( 1R, 5R)-1 -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 4-(2-(((S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-y 1)- 8 -fluoropy ri do [4,3 -d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol IUPAC Name 4-(2-(((R)-2- (difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-( 1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthal en -2-ol 4-(2-(((R)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy )-4-(( 1 S,5 S)-1 -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 4-(2-(((R)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((5R)-1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-y 1)- 8 -fluoropy ri do [4,3 -d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol IUPAC Name 4-(4-(1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3 -yl)-8-fluoro-2-((6'-methylenetetrahydrospiro[cy clopropane-l,3'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthal en -2-ol 2-amino-4-(6-(difluoromethyl)-4-( 1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 2-amino-4-(6-chloro-4-(l -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile IUPAC Name (S)-2-amino-4-(6-chloro-4- ((lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorob enzo [b ] thi ophene-3-carbonitrile (S)-2-amino-4-(6-chloro-4-((lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (R)-2-amino-4-(6-chloro-4-((lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile # Structure IUPAC Name 113 H        ZF N            N NH2 / \ k k 1     / \ O Ml (R)-2-amino-4-(6-chloro-4-((lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorob enzo [b ] thi ophene-3-carbonitrile 114 H       ZF N N__A f F             N F—d       U\z^x / C| m kM      A /        ks. J<5x k     k / NH2 \ xov y\ ZM N >        O / \__ /          f <7 ys F 2-amino-4-(6-chloro-2-(((S)-2- (difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 115 H        / F r>____<g f F             N f~4     N^yv01 \\\ X / X 0          .., / M n x                         / \__ /          f < / ys F (R)-2-amino-4-(6-chloro-2-«(S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy )-4-(( 1S,5S)-1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile IUPAC Name (S)-2-amino-4-(6-chloro-2-(((S)-2-(difluoromethylene)tetrahydr o- lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl )-8-fluoroquinazolin-7-yl )-7-fluorobenzo[b]thiophene-3-carbonitrile (R)-2-amino-4-(6-chloro-2-(((S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(( 1R, 5R)-1 -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-7-fluorob enzo [b ] thi ophene-3-carbonitrile (S)-2-amino-4-(6-chloro-2-(((S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(( 1R, 5R)-1 -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 2-amino-4-(4-( 1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile # Structure IUPAC Name 120 H        zF K__Z f F /     Ax Ax A A / NH2 \ X o ^N   X^^X^ \____y          f Z ys F (R)-2-amino-4-(4-((lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 121 H        zF on N          F P        1     AFn /     A> Ax A A / Nh2 \   O    Y^X ZX< \___ /              F <7 F (R)-2-amino-4-(4-(( 1S, 5 S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 122 H        zF ,N x / ^X K__Z f F f         1     AFn / \^x A> Ax A A / Nh2 \    o n    X Zx^ N >               1      / / "'"€ 1 \ /          F ( / V-S F (S)-2-amino-4-(4-((lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 123 IUPAC Name (S)-2-amino-4-(4-((l S, 5 S)-1 -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 124 4-(4-(1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2S,3R,6S,7aS)-6-fluoro-2-(fluorom ethyl )-3-phenyltetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 125 4-(4-(1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6’5*,7a’7?*)-6'-fluorotetrahydrospiro[cyclop ropane-1,3 '-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 126 127 128 Structure IUPAC Name 4-(4-(1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-(thiophen-3 -yl)tetrahydro-1H-pyrrolizin-7a(5H)-y l)methoxy )py ri do [4,3 -d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 4-(2-(((2S,3R,6S,7aS)-3- (2,2-Difluorobenzo[d][l,3]dioxol-5-yl)-6-fluoro-2-(fluoromethyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 2-amino-4-(6-chloro-2-(((R)-2- (difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(l-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-7-fluorob enzo [b ] thi ophene-3-carbonitrile 129 130 IUPAC Name 2-amino-4-(2-(((S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 4-(2-((6'-(difluoromethylene)tetrahydr ospiro[cyclopropane-l,3'-pyrrolizin]-7a'(5'H)-yl)methoxy)-4-( 1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0468] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0469] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.

[0470] In some embodiments, the compound is a salt of any acid described in the Table 2 and any one of the compounds described in Table 1.

[0471] Table 2 Pharmaceutical acceptable acid forming salts with the Compound of Formulas (A). 1 -hydroxy-2-naphthoic ethanesulfonic acid; methanesulfonic acid; acid; formic acid; naphthalene-1,5 -di sulfonic 2,2-dichloroacetic acid; fumaric acid; acid; 2-hydroxy ethanesulfonic galactaric acid; naphthal ene-2-sulfonic acid; gentisic acid; acid; 2-oxoglutaric acid; glucoheptonic acid (D); nicotinic acid; 4-acetamidobenzoic acid; gluconic acid (D); nitric acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-1 O-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecyl sulfuric acid; ethane-l,2-disulfonic acid; glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p)', undecylenic acid

[0472] In some embodiments, the compound is a salt of acetic acid and any one of the compounds described in Table 1.

[0473] In some embodiments, the compound is a salt of adipic acid and any one of the compounds described in Table 1.

[0474] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1.

[0475] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1.

[0476] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.

[0477] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 1.

[0478] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds described in Table 1.

[0479] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 1.

[0480] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 1.

[0481] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.

[0482] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0483] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0484] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0485] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0486] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0487] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0488] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0489] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0490] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (IV) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (IV). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from 2H, 13C, 14C, 15N, 18O, 29Si, 31P, and 34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with 2H with regard to one or more atoms thereof).

[0491] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0492] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0493] In some embodiments, the compound is a deuterium labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0494] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1.

[0495] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0496] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[0497] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a nondeuterium labeled reagent.

[0498] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0499] In some embodiments, the compound is a 18F labeled compound.

[0500] In some embodiments, the compound is a 33S labeled compound, a 34S labeled compound, a33 S labeled compound, a 36S labeled compound, or any combination thereof.

[0501] It is understood that the 18F, 33S, 34S, 33S, and / or 36S labeled compound, can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a 18F, 33S, 34S, 35S, and / or 36S labeled reagent for a non-isotope labeled reagent.

[0502] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned 18F, 33S, 34S, 35S, and 36S atom(s) is within the scope of the disclosure. Further, substitution with isotope (e.g,, 18F, 33S, 34S, 35S, and / or 36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0503] For the avoidance of doubt, it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0504] The various functional groups and substituents making up the compounds of the Formula (IV) are typically chosen such that the molecular weight of the compound does not exceed 1000 Daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 Daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 Daltons or less, for example 500 Daltons or less, for example 450 Daltons or less.

[0505] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0506] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0507] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0508] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0509] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chern. 1966, 78, 413; Cahn and Ingold, J. Chern. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964,41, 116).

[0510] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0511] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0512] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0513] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0514] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0515] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0516] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0517] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (5)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity.

[0518] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0519] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g, trifluoroacetate).

[0520] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0521] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0522] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0523] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

[0524] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0525] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0526] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.

[0527] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0528] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of present disclosure include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (IV). Examples of tautomeric forms include keto-, enol- , and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. H / 0       \ OH H+ x 0’ —c-c' c=cz — c=cz | \ / \ H+ / \ keto              enol                   enolate

[0529] Compounds of any one of the Formulae disclosed herein containing an amine function may also form A-oxides. A reference herein to a compound of Formula (A) that contains an amine function also includes the A-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an A-oxide. Particular examples of A-oxides are the A-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. A-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxy carb oxy lie acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, A-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0530] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.

[0531] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically produced compound or a metabolically-produced compound.

[0532] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0533] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include Ci-Cio alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-Cio alkoxy carbonyl groups such as ethoxycarbonyl, V,V-(Ci-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, V-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(Ci-C4 alkyl)piperazin-l-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0534] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-A-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-Ci-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0535] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl,                      A-alkylaminomethyl,                      N,N- dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl       and 4-(Ci-C4 alkyl)piperazin-1 -ylmethyl.

[0536] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug). Method of Synthesizing the Compounds

[0537] The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

[0538] The compounds of Formula (IV) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (IV). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

[0539] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of Compounds

[0540] The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Suitable methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Procedures which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below. GENERAL PROCEDURE

[0541] In general, the compounds of present invention can be prepared using sequences of reactions presented at the Scheme 1.

[0542] Scheme 1

[0543] It must be understood that any of the compounds at the Scheme 1, any of substituents in these compounds can be further modified at any step of presented sequences to provide modified derivatives of these compounds useful for preparation of compounds of present disclosure.

[0544] All reagents may be commercially available compounds itself or products of synthesis from commercially available reagents. For preparation these reagents may be used one step or multi step synthetic procedures, including but not limited procedures described herein in preparative part.

[0545] It should be obvious for specialist in this field that any of compound of the present invention obtained according to the procedures described above may be a subject for further transformation and modification that will let to obtain other compound of the invention. Biological Assays

[0546] Compounds designed, selected and / or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0547] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0548] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. Pharmaceutical Compositions

[0549] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0550] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0551] Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0552] Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0553] The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0554] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0555] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0556] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, randomly methylated-P-cyclodextrin, ethylated-P-cyclodextrin, triacetyl-P-cyclodextrin, peracetylated-P-cyclodextrin, carboxymethyl-P-cyclodextrin, hydroxyethyl-P-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-P-cyclodextrin, glucosyl-P-cyclodextrin, sulfated P-cyclodextrin (S-P-CD), maltosyl-P-cyclodextrin, P-cyclodextrin sulfobutyl ether, branched-P-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly methylated-y-cyclodextrin, and trimethyl-y-cyclodextrin, and mixtures thereof.

[0557] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, di sodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0558] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0559] In some embodiments, examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0560] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. In some embodiments, the tonicity agent is selected from the group consisting of a glycol (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0561] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0562] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0563] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and s-aminocaproic acid, and mixtures thereof.

[0564] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylenepolyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, poly oxy ethyl enated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0565] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0566] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0567] In some embodiments, a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.

[0568] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0569] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0570] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a KRAS(G12D) related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0571] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat an KRAS(G12D) related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0572] The size of the dose for therapeutic or prophylactic purposes of a compound of present disclosure will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well-known principles of medicine. Methods of Use

[0573] In some aspects, the present disclosure provides a method of inhibiting of KRAS(G12D) (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0574] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0575] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0576] In some embodiments, the disease or disorder is associated with KRAS(G12D). In some embodiments, the disease or disorder is a disease or disorder in which KRAS(G12D) is implicated.

[0577] The compounds of the invention are also useful in treating diseases associated with KRAS(G12D). For example, diseases and conditions treatable according to the methods of the invention include Lung Cancer (LNCR); Pancreatic Cancer (PNCA); Colorectal Cancer (CRC); Adenocarcinoma; Gastric Cancer (GASC); Breast Cancer (BC); Noonan Syndrome 1 (NS1); Lung Cancer Susceptibility 3 (LNCR3); Ovarian Cancer (OC); Juvenile Myelomonocytic Leukemia (JMML); Leukemia, Acute Myeloid (AML); Cardiofaciocutaneous Syndrome 1 (CFC1); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Myeloma, Multiple (MM); Leukemia, Chronic Myeloid (CML); Lynch Syndrome (HNPCC); Hepatocellular Carcinoma (HCC); Melanoma; Prostate Cancer (PC); Esophageal Cancer (ESCR); Familial Adenomatous Polyposis (FAP); Costello Syndrome (CSTLO); Skin Melanoma; Gastrointestinal Stromal Tumor (GIST); Tatton-Brown-Rahman Syndrome (TBRS); Mismatch Repair Cancer Syndrome 1 (MMRCS1); Glioma Susceptibility 1 (GLM1); Retinoblastoma (RBI); Brain Cancer; Squamous Cell Carcinoma, Head and Neck (HNSCC); Down Syndrome; Tuberous Sclerosis 1 (TSC1); Deficiency Anemia; Multiple Endocrine Neoplasia, Type I (MEN1); Medulloblastoma (MDB); Hypertension, Essential (EHT); Fanconi Anemia, Complementation Group a (FANCA); Type 2 Diabetes Mellitus (T2D); Amyotrophic Lateral Sclerosis 1 (ALS1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0578] In some embodiments, the disease or disorder is a Lung Cancer (LNCR).

[0579] In some embodiments, the disease or disorder is a Pancreatic Cancer (PNCA).

[0580] In some embodiments, the disease or disorder is a Colorectal Cancer (CRC).

[0581] In some aspects, the present disclosure provides a method of treating or preventing a Lung Cancer (LNCR) in a subj ect in need thereof, comprising administering to the subj ect a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0582] In some aspects, the present disclosure provides a method of treating a Lung Cancer (LNCR) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0583] In some aspects, the present disclosure provides a method of treating or preventing a Pancreatic Cancer (PNCA) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0584] In some aspects, the present disclosure provides a method of treating a Pancreatic Cancer (PNCA) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0585] In some aspects, the present disclosure provides a method of treating or preventing a Colorectal Cancer (CRC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0586] In some aspects, the present disclosure provides a method of treating a Colorectal Cancer (CRC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0587] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting of KRAS(G12D) (e.g., in vitro or in vivo).

[0588] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0589] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0590] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a Lung Cancer (LNCR) in a subject in need thereof.

[0591] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a Pancreatic Cancer (PNCA) in a subject in need thereof.

[0592] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a Colorectal Cancer (CRC) in a subject in need thereof.

[0593] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating Lung Cancer (LNCR) in a subject in need thereof.

[0594] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating Pancreatic Cancer (PNCA) in a subject in need thereof.

[0595] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating Colorectal Cancer (CRC) in a subject in need thereof.

[0596] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting of KRAS(G12D) (e.g., in vitro or in vivo).

[0597] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0598] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0599] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Lung Cancer (LNCR) in a subject in need thereof.

[0600] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Pancreatic Cancer (PNCA) in a subject in need thereof.

[0601] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Colorectal Cancer (CRC) in a subject in need thereof.

[0602] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Lung Cancer (LNCR) in a subject in need thereof.

[0603] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Pancreatic Cancer (PNCA) in a subject in need thereof.

[0604] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Colorectal Cancer (CRC) in a subject in need thereof.

[0605] The present disclosure provides compounds that function as inhibitors of KRAS(G12D) (e.g., in vitro or in vivo). The present disclosure therefore provides a method of inhibiting of BTK in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0606] In some embodiments, the inhibitor of KRAS(G12D) is a compound of the present disclosure.

[0607] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays / disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.

[0608] The present disclosure also provides a method of treating a disease or disorder in which KRAS(G12D) is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0609] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Routes of Administration

[0610] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0611] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. EXAMPLES General synthetical procedures and examples of the compound’s preparation.

[0612] All reagents were commercial and were used without further purification. Yields refer to purified and spectroscopically pure compounds. 1H NMR spectra were recorded using Bruker AVANCE III 400 MHz and TMS was used as an internal standard. The LCMS measurement was performed using Agilent 1260 series LC / Mass system operating in ES (+) or (-) ionization mode; T = 30°C; flow rate = 1.5 mL / min; detected wavelength: 214 nm and 254nm. LC detector : diode-array detector (DAD) or photo-diode array detector (PDA) or variable wavelength detector (VWD); Mass detector: SQ Detector or SQ Detector 2 (electrospray ionization source); Column : Sunfire C18 column (5 pm, 4.6 x 50 mm) or Waters Acquity UPLC BEH C18 column (1.7 pm, 2.1 x 50 mm).

[0613] Abbreviations used in the following examples and elsewhere herein are: 2-MeTHF ACE-CI ACN 2-methyl tetrahydrofuran 1-chloroethyl chloroform ate acetonitrile aq. anh. atm BAST BI-DIME aqueous anhydrous atmosphere bi s(2-m ethoxy ethyl )aminosulfur tri fluoride 3-(feH-buty 1)-4-(2,6-dimethoxypheny 1)-2,3-dihy drobenzo[t / ] [1,3 ]oxaphosphole br. BuLi cataCXium A Pd G3 broad butyl lithium mesylate[(di(l-adamantyl)-n-butylphosphine)-2-(2'-amino-l, 1 '- biphenyl)]palladium(II), [(Di(l-adamantyl)-butylphosphine)-2-(2'- amino-1,1 '-biphenyl)]palladium(II) methanesulfonate DAST DCE DCM DEA DIPEA DMF DMSO DPEphosPdCh EA ESI h HPLC IPA LCMS LHMDS m M MHz diethylaminosulfur trifluoride dichloroethane di chloromethane diethylamine A, A-di i sopropy 1 ethyl amine A,A-dimethyl formamide dimethyl sulfoxide dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) ethyl acetate electro spray ionization hour(s) high pressure (or performance) liquid chromatography isopropyl alcohol liquid chromatography mass spectrometry lithium bis(trimethylsilyl)amide multiplet molar megahertz min MOP NMMO NMR PE minutes (2'-methoxy-l,l'-binaphthalen-2-yl)(diphenyl)phosphane N-methylmorpholine N-oxide nuclear magnetic resonance petroleum ether ppm PyBOP rt Rt parts per million benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate room temperature retention time RuPhos-Pd G2 s SCXRD SFC sat. TBS TEA TFA THF TLC TTIP VCD Xphos Xphos Pd G3 chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-l,r-biphenyl)[2-(2'-amino-l, 1 '-biphenyl)]palladium(II), RuPhos-Pd-G2 solid single crystal X-ray diffraction supercritical fluid chromatography saturated to7-butyldimethyl silyl tri ethylamine trifluoracetic acid tetrahydrofuran thin-layer chromatography titanium tetraisopropoxide vibrational circular dichroism dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,r-biphenyl]-2-yl]phosphane (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) methanesulfonate, XPhos-G3-Palladacycle Examples of the Final Compound

[0614] In the Table 3 presented analytical data for certain non-limiting examples of the compound of Formula (IV).

[0615] Table 3 Selected examples of the compound of Formula (IV) # Structure [MH]+ Calc. [MH]+ Found a H kJ F F              N LILL i rA U J O OH                F 663.2507 663 # Structure [MH]+ Calc. [MH]+ Found 1 N              F 'i—\^ A J. A A J 663.2507 663 N^ /        । J \              r    Xz OH 2 H _ / F \_ /   F CW / a O     ' 1 F OH 663.2507 663 3 H _ zF N C_Z F F^     N^y^N NO      F N cf3 nh2 653.2587 653 # Structure [MH]+ Calc. [MH]+ Found 4 H _ / F k_Z F \                     cf3 OM / Wy N       7                          1 II \ /             F nh2 653.2587 653 5 H      zF €-0 N \                   F3C / \ A A .A A. x A o  y x y N )                   ।      J \___ /             F nh2 657.2336 657 6 N \                    F3C a X jl a^f x >x 0 n       ii N 7                          1 II \ /             F nh2 657.2336 657 # Structure [MH]+ Calc. [MH]+ Found b H L J F N N=i HN V k L k      / \ Ik J o 1                                     F 623.287 623 7 H       / F £__Z F /       1 Z JL L NH < J<f^O N       11 O F JU 623.287 623 8 H       / F ^NxU55^ 1_Z F \     NZ\ / ^N / \ J J        / NH x >\ o n'yyV O J JU 623.287 623 # Structure [MH]+ Calc. [MH]+ Found 9 H     / (“0 N \                    / =N /        JI JL JL >< NH O ' JU F 627.2619 627 10 H _ U \_ /   F / \ JI 2 JJ r NH x J\ 0 n       ii xr O JU F 627.2619 627 11 O Hx    / "^\ Z     Z   ZI #   \ / / , / / —"n'^X /                   T| -n      cn z hO 645.2183 645 # Structure [MH]+ Calc. [MH]+ Found 12 H    Z k_Z F F                         / ^2 '        II ll N=( NO f kA 645.2183 645 c H F^^N. F kJ N        N 1                    nh2 N^ik^N rk r~~\ jl IL Ji 7 ?s L /    J U< '---- /                                        F F 669.2183 669 13 __ ___Z I O Xz\ zr\ z     z   ZI __ff    \ 7 / , / m_O j )—z     ■n'^x Z~v r=<l -n i N) 669.2183 669 # Structure [MH]+ Calc. [MH]+ Found 14 H       / F \_Z F N 1      X nh2 N\ /       F LI 669.2183 669 15 H__ / N         N. 1       x nh2 \      N        \=Y n^i^yys NO ' V* 651.2277 651 16 H       / F Ik__Z F N 1               nh2 \ \==( 651.2277 651 # Structure [MH]+ Calc. [MH]+ Found 17 '__z | d / ^\ Z     z   ZI __U    \ / ,. / CO       A —'            Ji O    / z     TT^X \___ /                -n v / j X'z I 702.254 702 18 H     / / N / U _Z F / \ Jj 2        1 NH O J JU '—'           f3c y 702.254 702 19 h _ / F N 7U / =N' N H NO ' AJ 677.2587 677 # Structure [MH]+ Calc. [MH]+ Found 20 H       / F Ik__Z F N N H O   ' AJ Fs^y 677.2587 677 21 Ll_---V        7----k \    /  \\ X / \ / O r vv ( / \ / — AV\ XZ   Z—(Z   Z W \=( o 1 Z — 662.2554 662 22 H      zF k,___ / | F F NO ' u OH 662.2554 662 # Structure [MH]+ Calc. [MH]+ Found 23 H       / F £__Z F F^ CF3 N       7                         1         II \ /        F  N^1 nh2 652.2635 652 24 H      zF zNx / Y Ik__Z F ^hF \                    CF3 AaAV N     )                  1 J \___ /               F nh2 652.2635 652 25 H      ZF N \                     CF3 a IJULf <        0 N         li YT N 7                          1 II \ /              F nh2 656.2384 656 # Structure [MH]+ Calc. [MH]+ Found 26 H      zF _Z F \                     cf3 /      JL A X / F <         0 N           Il nr N >                     1 II \ /              F nh2 656.2384 656 27 H _ / F &__Z F \    nX^ 1 NO    F IJ C / n-nh 622.2917 622 28 H _ zF |k__Z F 1 NO ' JU C / N-NH 622.2917 622 # Structure [MH]+ Calc. [MH]+ Found 29 H      zF N O ' JU N-NH 626.2667 626 30 H       / F _Z F \    N^A I O F JU N—NH 626.2667 626 31 Cxi X ZX^,(Z)     U- / u.                     7 ' A / ^A # 4 IZ   H \   H \AV H=^ o 1 644.2231 644 # Structure [MH]+ Calc. [MH]+ Found 32 H       / F \_Z F F                                / NH2 111 w L /     J kX 644.2231 644 33 z | o' H. / ^\ z     z   ZI %__# \ / / ,. / m y7 X Wx -n z ro 668.2231 668 34 H      zF Ik__Z F N 1 \ nh2 N\ / f kX 668.2231 668 # Structure [MH]+ Calc. [MH]+ Found 35 □Z u. \__l_L        ___ / C CV IZ  Z— o 1 650.2325 650 36 H      zF _Z F ^NT      N 1                    nh2 A m H \ Jk U\ U NO F kJ 650.2325 650 37 H _ zF b__Z F k             \=N / \ JU 2            NH O f JU '--'             F3c J 701.2587 701 # Structure [MH]+ Calc. [MH]+ Found 38 H       / F H F N    % \    nA / X \^N 7 \ 1 JL JL 'nh O   F JU '—'          f3u y 701.2587 701 39 H       / F N r-\ . JI 1     1 4 NV /       F I J F3cr 676.2635 676 40 H       / F ^NxV^y Ik__Z F "K      i’kI / =^ CUo^nUUU'nh O   F IT 676.2635 676 # Structure [MH]+ Calc. [MH]+ Found e H       >F \___ / |      F ... 1                              F F<                             Hl 1 O^aZX jm NO J Tj OH 696.2164 696 41 H       / F £__Z F \ na^yci /       / X            / °H X / < o N vJ y / J 696.2164 696 42 __ r"H 1 C) Z\ >— Z 1 zi m    -Ti—\   X w \ Q   m o i 696.2164 696 # Structure [MH]+ Calc. [MH]+ Found 43 Y N /               / X    ^NH2 O   AJ fY Y 686.2245 686 44 H       / F / N _Z F F                         / 01 \   n y Y /        JL              .NH2 <     n ^rY Y NO ' AJ '—'         f3ct Y 686.2245 686 45 H      zF £“0 N F           / V / 01 \   n y Y /                              ,NH2 N\ /       F LJ '--'           F3c Y F 690.1994 690 # Structure [MH]+ Calc. [MH]+ Found 46 H       / F Ik___ / | F /                              .nh2 < ><o n      Y N\ /      F JO '—'          f3(T y F 690.1994 690 47 H        ,F €-0 N \    nUyCI r=N X >X 0 N T Y V NO 656.2527 656 48 H      zF 6Y N F                                 M Y        N            / ^N / \ JI 2 JJ I NH O f JU 656.2527 656 # Structure [MH]+ Calc. [MH]+ Found 49 H      ZF N \   nV / ' n \       o n         ii o ' jy F 660.2276 660 50 H    7 Ik__ / ] F \       N / \ i          r nh A 7C o n      ii o j jy F 660.2276 660 51 CN T ZX^-C0    ll u- V vv " / 7^ / / \ ■EZ.     ~z.—Z \=< o [ z— 678.1841 678 # Structure [MH]+ Calc. [MH]+ Found 52 H       / F \_Z F F-              -A \__ N           N=y nA f kA 678.1841 678 53 H       / F £__Z F UU    N N             W\ nWU! / \>\ jz JkkkuCu N\ / J LI '-----'                                             F 702.1841 702 54 H _ / F xNx / ^\ /       JLJLuC / s x       o n             if o m '----'                                          F 702.1841 702 55 H      zF UN F     U^CIUNH2 /       JLkkyC / s X >X 0 N           if NO f u 684.1935 684 # Structure [MH]+ Calc. [MH]+ Found 56 H       / F 1_Z F F                                   / 2 \         n            >=< /         JL JL ^C\)s <         o n                 ii O ' U1 684.1935 684 57 H      ZF 1 \     N       Vn / \^. JJ J JL >< .nh N\ / J AJ \— /          f3ct y 735.2197 735 58 H      ZF Ik__Z F < >     N 1                         \\\ n^v^Vci / \      J J        1  NH N\ /      F JU '—f           f3ct y 735.2197 735 # Structure [MH]+ Calc. [MH]+ Found 59 H      zF N N / \               II                            1 r3 NO aj N-NH 710.2245 710 60 H _ / F 1_Z F ^hF F N              CFo / -----\               II                           1 '3 O I aX / N—NH 710.2245 710 61 H      zF bZ F 1                                                                 1 A^ooi O ' u OH 680.246 680 # Structure [MH]+ Calc. [MH]+ Found 62 H      zF Ik__Z F 1            1 1 O J U OH 680.246 680 63 H       / F £__Z F F A            I              CF3 N       7                          1 II \ /             F nh2 670.254 670 64 H      zF k_Z F F \         N            CF3 N       7                          1 II \ /             F nh2 670.254 670 # Structure [MH]+ Calc. [MH]+ Found 65 H       / F £__Z F / \     JI               ,NH2 O ' JU '—I         f3c^ y F 674.2289 674 66 H       / F N \ nUvF rK^NUY^Y^ O   JU F 674.2289 674 67 / ^X1 C) / F\ z / —Z   ZT H     \ 7 / ,. / OU U \U~i \'z I 640.2823 640 # Structure [MH]+ Calc. [MH]+ Found 68 H _ / F V_Z F i NO ' JU C T N—NH 640.2823 640 69 H      zF £-0 N \    n AyF | O   JU N-NH 644.2573 644 70 H _ zF _Z F \    tiAyf , OozAAX^ NO ' JU C / n-nh 644.2573 644 # Structure [MH]+ Calc. [MH]+ Found 71 __ z ] oz / ^\ z     Z   ZI #   \ h,J /  \     "n—x / v m    m \    T'-'Z m     co z NJ 662.2137 662 72 H    7 k_Z F F                               NH2 NO    F kA 662.2137 662 73 H _ / F N C__Z F V             \W F      X^ / F \ / H2 / X XXkXZ / s N\ / f UI 686.2137 686 # Structure [MH]+ Calc. [MH]+ Found 74 H       / F Ik__Z F F      X^ / F \ VNH2 / X JLX. N\ /       F LI 686.2137 686 75 H _ / F N £__Z F F      X^ / F \ / H2 i x xJL^xX / s O F kJ 668.2231 668 76 H      zF xN'V / S5\ Ik__Z F n ?              \W F       X^ / F \ / NH2 N^^^^X^X / 8 O    F kJ 668.2231 668 # Structure [MH]+ Calc. [MH]+ Found 77 H    7 £__Z F N \       N\=N / \      1 3       L ,NH NO ' JU '--'             F3C J 719.2493 719 78 H       / F N \   nVV Un / \ i JL u 7h x  ony X V N\ /      F JU \— /        f3u y 719.2493 719 79 H       / F _Z F F                  ^F Uy JL jfl fF3 O f rj % / N—NH 694.254 694 # Structure [MH]+ Calc. [MH]+ Found 80 H       zF Ik__Z F F        xx / X / F n        nK  cFo / —\       II             i3 O J AJ ( / N-NH 694.254 694 81 H    7 £__Z F F         xL XX / CF3 \      N / \>\ Jx          ^OH NO F^5^ 730.2428 730 82 H      / N F          xL     / CF3 / \^X x^L            / OH X XX 0 N NO J k) 730.2428 730 # Structure [MH]+ Calc. [MH]+ Found 83 H       / F N F \      n /       JL JL JL .NH2 N\ /      F JU '—         f3c T 720.2508 720 84 uF N F         / V UF3 \       N /       JL             ^NH2 O   F XJ '--'            F3c y 720.2508 720 85 H      zF _Z F F           / L     / CF3 Y    Nxy Y /                             ,NH2 x X ° n     Y N\ /      F JU '—         f3c J F 724.2258 724 # Structure [MH]+ Calc. [MH]+ Found 86 H _ / F .N AV Nk__Z F F          xL     / CF3 \      N /        JL               ,NH2 C J<0 N     Y O ' JU --             F3C J F 724.2258 724 87 H       / F £__Z F a5oCl 9U\v N-NH 690.2791 690 88 H _ / F Ik__Z F F          xL     / CF3 U          N             1 O^o^n^yY^U NO JU n-nh 690.2791 690 # Structure [MH]+ Calc. [MH]+ Found 89 N NO f LJ N-NH 694.254 694 90 H       / F N \ n^VYCF| NO J JU N-NH 694.254 694 91 ^z | oz )=z z     z   ZI __ / /   \ h,J " vy J / \      T1— X / —ni / /        __ co \ W 1 -n I hO 712.2104 712 # Structure [MH]+ Calc. [MH]+ Found 92 ^,CF3 / NH2 1 H f A. jC F 712.2104 712 N \    nA' N / 93 H       / F £_Z F F,       „ / L^. / CF3 736.2104 736 <•,                          IN 1! , NO ' JUl '—'      n=—Z >r f / s h2n 94 H N \    nA Oz°^n^ N / '---- N F F ^% / CF3 uQ =-Z F / S h2n 736.2104 736 # Structure [MH]+ Calc. [MH]+ Found 95 H       / F £_Z F N N                     Ill 1       CP    NH2 F               / Ak            1    / z \        N            }=< / \>Ax JZXLXZ / 8 O   f u 718.2199 718 96 CM X z « T>A / u.       q )=7 C vv iz J H—\ \^- / H=^ O 1 718.2199 718 97 H       / F &__F < >     N 1 \      n / K / \CF3 \^n / \        JI J              NH O ' JU '—'          f3c y 769.2461 769 # Structure [MH]+ Calc. [MH]+ Found 98 H       / F N F^,                           \=n / \      1 1        / NH O   F JU '—'           f3c y 769.2461 769 99 H       / F £__Z F ^bT F                Uf3 \=n O     f' I J '—'           f3(T 744.2508 744 100 H       / F __ / [    F F            x-L      / CF3 11                  / =Nt O    I I j '—'           f3ct 744.2508 744 # Structure [MH]+ Calc. [MH]+ Found 101 H        ,F F             N               F F— / N'S /             F L J OH 693.2 693 102 H       ZF <--F F                              F a X X X X J N<s\           1 \ /     F AA OH 693.2 693 103 H       ZF .N E—'J f F                               F f— / a X XX X J N ' /            F L J OH 693.2 693 # Structure [MH]+ Calc. [MH]+ Found 104 H       ZF K___J F F                               F F—Z A                  n        n / ½ k k 1 1 \ xxo^N?YYkr N' /                F L J OH 693.2 693 105 H       ZF kk F F                               F F     N^k^ikyk / ^a k k !L 1 NO     u OH 693.2 693 106 H       ZF ,N^^===Z \__ /    F F                              F F V\     N^V^Nk^il / H    k k 1 1 U \ kkkD^N^Y^rii NO f o OH 693.2 693 # Structure [MH]+ Calc. [MH]+ Found 107 H       ZF N__J F F / X T 1. Ji f J jLy       f v                 OH 683.3 683 108 H k     F N         F 1                1 N. nxV'f \ / nh2 F                Z' \     O N CV F T' x N"X                  "-'^''"F 718.2 718 109 H kJ F N       Nx F.    X^K / NH2 / \      k L. Ji 1 s \ >c^o n kr      Il O ? 1XF 702.2 702 # Structure [MH]+ Calc. [MH]+ Found 110 H      / H F 702.2 702 E                            ri N II NHo >< NO I lX 111 H        zF N aXjC NO M N |l nh2 S 702.2 702 112 H        ZF V F aXX” NO J I! N II nh2 s F 702.2 702 # Structure [MH]+ Calc. [MH]+ Found 113 H      / N           N F                             0 NH2 h 111 >( O Ml 702.2 702 114 H       ZF N__A F F             N c /              1         ri N y_    N^y^yy \ /               JI k / NH2 \ / X Q n M^X / V n >        O J \__ /        f     ys F 732.2 732 115 H        / F F             N f-4      n<X^yci \\\ \ X cr M^vx ... / M N X             I Z X / \ y           f       2—s F 732.2 732 # Structure [MH]+ Calc. [MH]+ Found 116 H       ZF N sVy F F             N f~4     nAxaci \\\ /     A> A^ A A / NHo \__ /         f ( / yx F 732.2 732 117 H        / F ,N \ / y K A    F F             N f—4      X\ / ci \\\ /     Ax Ax A A / Nh2 \ A; cr          ..... N \             I     / / \ / __ /          f ( / y-s F 732.2 732 118 H        / F K__ / F F f~4 nAxci \\\ i     A> X A A / Nh2 \ >< o n^ \__ /         f ( / ys F 732.2 732 # Structure [MH]+ Calc. [MH]+ Found 119 O z   y—z 1 z t r-J   ° / / vV w V   / ^r— T|           Z T 736.2 736 120 H        ZF \_ /   F F r           1       YF N / \>*\         JI k .nh2 \ X o ^n N Y                         <Z F <y F 736.2 736 121 H        zF X N          F f          1      J^FN / \>*\       A x / Nh2 \ Jc o n X^X .XX N \          XX X \^j       f    ys F 736.2 736 # Structure [MH]+ Calc. [MH]+ Found 122 H        zF / N\Z^Z K_Z f F c         1      ZFN /            Uyx J-L         / NH2 \ 0\ O Y      .....Z^Z N \                / .....\   / \__ /         F Z V-S F 736.2 736 123 H        zF z—-T   f F c         1      ZFN \         N /              A    L / NH2 \ >< O ^N    \ Z^< n^\         1    / r"\ 1 \ /            F Z F 736.2 736 124 H >F N              F iVj O' ?        °" 771.3 771 # Structure [MH]+ Calc. [MH]+ Found 128 H       ZF N__ / F F             N c /             1        ri N \ii^ \ / \ As. A L .nh2 \__ /           F / F 732.2 732 129 H       ZF N__A f f c__ /             1            N “V nXv5 a /             JL x ^nh2 F / y-s F 766.2 766 130 H cd 'F F                                   । F F—1 .. L i f xx v                 OH 723.3 723 Synthesis of Building Blocks Synthesis of 4-(4-(l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)rnethoxy)pyrido[4,3-d]pyrimidin- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (P5) Cl Boc                        P1           Boc I                                                                                                                                                                                                                      I P4

[0616] Preparation 1. / tv?-Butyl l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Pl). To a solution of tert-butyl l-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 95 % purity, 3.94 mmol) and 2-((difluoromethyl)-(methylene)sulfinyl)pyridine (903.24 mg, 4.72 mmol) in DMF (40 mL) was added dropwise 1.0 M solution of potassium 2-methylpropan-2-olate in THF (7.87 mL, 7.87 mmol ) at -50°C for 1 h. The reaction mixture was stirred for 2 h at -30°C, quenched with saturated aq. ammonium chloride solution (7.87 mL) and 6.0 M hydrochloric acid (7.87 mL), then stirred for 2 h at 60°C, and washed with EA (3 x 20 mL). The aq. layer was alkalized with sat. sodium bicarbonate and extracted with DCM (3 x 20 mL). Combined organic layers were washed with brine, dried over anh. Na2SO4. filtered, and concentrated under reduced pressure to afford the crude product (Pl) that was used for the next step without further purification. Yield 500 mg (23 %, purity 50 % by 'HN.V1R) as a brown oil. LCMS: Rt = 0.843 min; (ESI) [M+H]+ calc, for Ci3H2iF2N2O2+ 275.16, found 275.1. ‘HNMR (400 MHz, CDCh), 5: 4.42 (d, J =27.2 Hz, 1H), 3.95 - 3.68 (m, 2H), 3.50 (d, J =13.2 Hz, 1H), 2.95 - 2.76 (m, 2H), 2.90 -1.95 (m, 1H), 1.92 - 1.85 (m, 1H), 1.79 - 1.62 (m, 2H), 1.40 (s, 9H).

[0617] Preparation 2. / ert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P2). A solution of DIPEA (353 mg, 2.73 mmol) in DCM (1 mL) was added to a stirred mixture of / ert-butyl l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Pl, 500 mg, 50 % purity, 0.91 mmol) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (299.1 mg, 1.18 mmol) in DCM (15 mL) at - 40°C. The reaction mixture was stirred at 25°C for 16 h, quenched with water (20 mL), and extracted with DCM (3 x 20 mL). Combined organic layer was washed with brine, dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using mixture of EA (0 to 50%) and petroleum ether as an eluant to afford 300 mg (60 %) of the title compound (P2) (90 % purity by LCMS) as a colorless solid. LCMS (ESI): Rt = 1.368 min, [M+H]+ calc, for C2oH2iC12F3N502+ 490.10, found 490.1. 'H NMR (400 MHz, CDCh), 5: 8.87 (s, 1H), 5.08 (d, J =28.8 Hz, 1H), 4.64 - 4.61 (m, 2H), 4.45 (d, 7=6.0 Hz, 1H), 3.87 (d, 7=12.4 Hz, 1H), 3.71 (d, 7=12.8 Hz, 1H), 2.15 - 2.04 (m, 2H), 1.68 - 1.60 (m, 2H), 1.53 (s, 9H).

[0618] Preparation 3. tert-Butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (P3). To a stirred mixture of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (P2, 300 mg, 90 % purity, 0.55 mmol) and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (263 mg, 1.65 mmol) in 1,4-dioxane (2 mL) was added DIPEA (214 mg, 1.65 mmol) at rt. The reaction mixture was stirred at 90°C for 16 h, quenched with water (20 mL), extracted with EA (3 x 20 mL). The organic layer was washed with brine, dried over anh. Na2SO4, fdtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (PE : EA = 1: 1) to afford 290 mg (72 %) of the title compound (P3) (83 % purity by LCMS) as a colorless solid. LCMS: Rt = 1.225 min, (ESI) [M+H]+ calc, for C28H34C1F4N6O3+613.23, m / z found 613.3. 'H NMR (400 MHz, CDC13), 5: 8.74 (s, 1H), 5.32 (d, J =53.6 Hz, 1H), 5.13 (d, 7=30.4 Hz, 1H), 4.62 - 4.57 (m, 1H), 4.45 - 4.03 (m, 2H), 4.34 - 4.26 (m, 1H), 3.80 (dd, 7=12.4, 4.4 Hz, 1H), 3.67 - 3.63 (m, 1H), 3.49 - 3.19 (m, 4H), 3.08 -2.97 (m, 1H), 2.35 - 2.12 (m, 4H), 2.05 - 1.89 (m, 4H), 1.69- 1.56 (m, 2H), 1.53 (s, 9H).

[0619] Preparation 4. / ert-Butyl l-(2,2-difluorovinyl)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (P4). A degassed mixture of tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P3, 290 mg, 83.4 % purity, 394.5 pmol), ((2-fluoro-6-(methoxymethoxy )-8-(4,4,5,5-tetramethyl-1,3,2-di oxaborolan-2 -yl)naphthalen-l-yl)ethynyl)triisopropylsilane (303.3 mg, 591.8 pmol), cataCXium A-Pd G3 (28.7 mg, 39.5 pmol) and potassium phosphate tribasic (251.2 mg, 1.18 mmol), 1,4-dioxane (6 mL), water (1.5 mL) was stirred in nitrogen atm at 100°C for 3 h, cooled, to ambient temperature, poured into water (10 mL), and extracted with EA (3 xlO mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, fdtered and concentrated. The residue was purified by silica gel column chromatography (PA : EA = 1:1) to afford 290 mg (69 %) of the title compound (P4) (90 % purity) as a yellow solid. LCMS: Rt = 1.581 min; (ESI) [M+H]+ calc, for C51 FWsNcOsSi 964.46, found 964.5. *H NMR (400 MHz, CDC13), 8: 9.09 (s, 1H), 7.80 - 7.77 (m, 1H), 7.51 (s, 1H), 7.37 - 7.34 (m, 1H), 7.31 - 7.26 (m, 1H), 5.59 - 5.23 (m, 3H), 5.19 - 5.04 (m, 1H), 5.00 - 4.49 (m, 3H), 4.46 - 4.18 (m, 2H), 4.10-3.95 (m, 1H), 3.88 - 3.56 (m, 1H), 3.51 (s, 3H), 3.49-3.41 (m, 1H), 3.31 -3.11 (m, 1H), 2.72 - 2.31 (m, 3H), 2.28 - 2.15 (m, 3H), 2.11 - 1.93 (m, 3H), 1.87 - 1.60 (m, 3H), 1.52 (s, 9H), 0.87 - 0.83 (m, 18H), 0.58 - 0.46 (m, 3H).

[0620] Preparation 5. 4-(4-(1-(2,2-Difluorovinyl)-3,8-diazabicyclo[3.2. l]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (P5). To a stirred solution of tert-butyl l-(2,2-difluorovinyl)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P4) (290 mg, 90 % purity, 0.27 mmol) in DCM (3 mL) was added 4M solution of HC1 in 1,4-dioxane (3 mL, 6.0 mmol) at 0°C. The reaction mixture was stirred at rt for 2 h and concentrated to afford 250 mg (97 %) of the title (P5) (86.4 % purity by LCMS) as a yellow solid that was used for the next step without further purification. LCMS: Rt = 1.086 min; (ESI) [M+H]+ calc, for C44H52F5N6O2SE 819.38, found 819.4.

[0621] Preparation 6. tert-Butyl (lR,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P6). Boc                   Boc P6 A mixture of BnBr (75.1 g, 439 mmol), tert-butyl (lR,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (78 g, 366 mmol), EtsN (74.0 g, 731 mmol), and ACN (1000 mL) was stirred at 20°C for 16 h, diluted with water (1000 mL), and extracted with DCM (2x800 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, and concentrated to afford the title compound P6 (122 g, 90% purity, 98.6% yield) as a lightyellow solid that was used for the next step without additional purification. 1H NMR (400 MHz, CDCI3), 5: 7.32 - 7.21 (m, 5H), 4.13 (d, J= 39.9 Hz, 2H), 3.47 (s, 2H), 2.60 (dd, J= 10.7, 2.5 Hz, 2H), 2.38 - 2.15 (m, 2H), 1.93 - 1.76 (m, 4H), 1.46 (s, 9H).

[0622] Preparation 7. tert-Butyl 3-benzyl-l-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P7). Boc                   Boc Bn                    Bn P6                 P7 To a solution of tert-butyl (lR,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P6, 122 g, 90% purity, 361 mmol) and A,A,A',A'-tetramethylethylenediamine (50.3 g, 433 mmol) in THF (1200 mL) was added dropwise 1.3 M s-BuLi (400 mL, 541 mmol ) at -40°C for 1 h. The reaction mixture was stirred for 1 h at -40°C, then DMF (79.1 g) was added dropwise at -30°C. The resulted mixture was allowed to warm to 0°C, stirred for 2 h, quenched with water (600 mL), and extracted with EtOAc (3x700 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a mixture of hexanes and EtOAc (10 to 100%) to give the title compound P7 (48 g, 90% purity by ^NMR, 36% yield) as a yellow solid. *HNMR (400 MHz, CDCI3), 8: 9.49 (d, J= 41.4 Hz, 1H), 7.36 - 7.23 (m, 5H), 4.19 (d, J= 62.3 Hz, 1H), 3.60 - 3.47 (m, 2H), 3.05 (d, J = 11.1 Hz, 1H), 2.59 (d, J= 11.2 Hz, 1H), 2.41 -2.21 (m, 2H), 2.06 - 1.89 (m, 4H), 1.44 (d, J= 12.4 Hz, 9H).

[0623] Preparation 8. tert-Butyl 3-benzyl-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (P8). O1.0 M t-BuOK.DMF, -50 °C ------------► NH4CI,6M HCI,60°C I Bn Boc I I Bn P8 To a solution of ZeH-butyl 3-benzyl-l-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P7 (48 g, 90% purity, 130 mmol) and 2-((difluoromethyl)-(methylene)sulfinyl)pyridine (30.1 g, 156 mmol) in DMF (500 mL) was added dropwise 1.0M solution of t-BuOK (234 mL, 234 mmol) in THF at -50°C for 1 h. The reaction mixture was stirred for 2 h at -50°C, quenched with sat. aq. solution of NH4CI (234 mL) and then 6.0 M aq. HC1, stirred for 16 h at 60°C, neutralized with sat. aq. solution of sat. NaHCOs, and extracted with EtOAc (3x400 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a mixture of Hexanes and EtOAc (10 to 30%) to afford the title compound P8 (25 g, 90% purity by 'H NMR, 47.3% yield) as a yellow oil. 1H NMR (400 MHz, CDCh), 5: 7.34 - 7.25 (m, 5H), 4.94 (d, J= 29.0 Hz, 1H), 4.21 (s, 1H), 3.50 (dd, J= 36.8, 13.3 Hz, 2H), 2.73 - 2.24 (m, 5H), 1.94 - 1.79 (m, 3H), 1.45 (s, 9H).

[0624] Preparation 9. 8-( / erLButyl) 3-(l-chloroethyl) l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.l]octane-3,8-dicarboxylate (P9). Boc                       Boc P8                        pg A mixture of to7-butyl 3-benzyl-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P8, 22 g, 90% purity, 54 mmol), ACE-CI (52.5 g, 367 mmol) and toluene (400 mL) was stirred at 120°C for 16 h, cooled, quenched with water (400 mL), and extracted with EtOAc (3x400 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a mixture of hexanes and EtOAc (5 to 20%) to afford the title compound P9 (8.0 g, 90% purity by 'H NMR, 35.0% yield) as a yellow oil. NMR (400 MHz, CDC13), 8: 6.60 (q, J= 5.6 Hz, 1H), 5.13 - 4.84 (m, 1H), 4.37 - 4.23 (m, 1H), 4.15 - 3.71 (m, 2H), 3.38 - 3.07 (m, 2H), 2.27 - 1.96 (m, 3H), 1.87 -1.80 (m, 3H), 1.72 - 1.56 (m, 1H), 1.47 (s, 9H).

[0625] Preparation 10. tert-Butyl l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Pl). Boc                     Boc P9                      P1 A solution of 8-(tert-butyl) 3-(1-chloroethyl) l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (P9, 8.0 g, 90% purity, 18.9 mmol) in MeOH (200 mL) was stirred at 60°C for 3 h, concentrated, diluted with sat. aq. solution of NaHCOs (50 mL), and extracted with EtOAc (40 mL*3). The organic layer was washed with brine, dried over anh. Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound Pl (5.0 g, 90% purity by 'HNMR, 86.2% yield) as a yellow oil. 1HNMR(400MHz, CDCI3), 8: 5.08 -4.85 (m, 7 = 29.7 Hz, 1H), 4.19 (d, J= 6.1 Hz, 1H), 3.20 (d, J= 12.5 Hz, 1H), 3.02 (d, J= 12.6 Hz, 1H), 2.75 (dd, J= 12.5, 1.9 Hz, 1H), 2.58 (dd, .1= 12.7, 1.8 Hz, 1H), 2.29 - 2.18 (m, 1H), 2.05 - 1.94 (m, 3H), 1.77 - 1.66 (m, 1H), 1.47 (s, 9H).

[0626] Preparation 11. tert-Butyl (lR,5R)-3-benzyl-1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P10 and tert-butyl (lS,5S)-3-benzyl-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate PH. Boc                             Boc            Boc I                                                                                                                                                                                                                         I                                                                                                          I \ / [     | Chiral sepration ly y[ ]   ,               | k J F           k J F O F N                               N              N I                                                                                                                                                                                                                         I                                                                                                          I Bn                               Bn              Bn P8                               P10             P11 A racemic mixture tert-butyl 3-benzyl-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P8, 3.0 g, 90% purity, 7.4 mmol) was separated by chiral Prep. HPLC using the following conditions: column Chiral ART Cellulose KCN 50 mm I.D. x 250 mm L (10pm), mobile phase: n-Hexane / IPA = 95% / 5% (V / V), temperature 25 °C, wavelength 254 nm. Enantiomeric purity of the separated enantiomers was determined using the following analytical method: column Chiral ART Cellulose KCN 5 pm 4.6 * 250 mm, mobile phase n-Hexane / IPA = 95% / 5% (V / V) at 1.0 mL / min, temperature 25 °C, wavelength 254 nm, back pressure 100 bar). Absolute configuration of the separated enantiomers was determined using VCD technology. Peak 2: tert-butyl (lR,5R)-3-benzyl-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P10. Yield 1.26 g (42%), 90% purity by HPLC, enantiomeric purity 100%) as a colorless oil. LCMS: Rt = 1.279 min; (ESI) calc, for C20H26F2N2O2 [M+H]+ 365.2, found 365.1. Chiral HPLC: Rt = 10.304 min. [a] D25 = +23.5 (c = 0.20, CHCI3). 1H NMR (400 MHz, CDCI3), 8: 7.31 - 7.30 (m, 4H), 7.25 - 7.24 (m, 1H), 4.98 - 4.91 (m, 1H), 4.21 (s, 1H), 3.54 (d,. / = 13.2 Hz, 1H), 3.45 (d, J - 13.2 Hz, 1H), 2.73 - 2.70 (m, 1H), 2.55 - 2.49 (m, 2H), 2.37 -2.35 (m, 1H), 2.27 - 2.24 (m, 1H), 1.96 - 1.76 (m, 3H), 1.45 (s, 9H); Peak 1: tert-butyl (lS,5S)-3-benzyl-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate PH. Yield 1.17g (39%), 100% purity by HPLC, enantiomeric purity 98.95%) as a colorless oil. LCMS: Rt= 1.274 min; (ESI) calc, for C20H26F2N2O2 [M+H]1 365.2, found 365.1. Chiral HPLC: Rt = 9.780 min (Method A). [a]D25= - 25.26 (c = 0.19, CHCI3). ‘HNMR (400 MHz, CDCI3) 8 7.31 - 7.30 (m, 4H), 7.26 - 7.22 (m, 1H), 4.98 - 4.90 (m, 1H), 4.25 - 4.16 (m, 1H), 3.54 (d, J = 13.2 Hz, 1H), 3.45 (d, J = 13.2 Hz, 1H), 2.73 -2.70 (m, 1H), 2.55-2.49 (m, 2H), 2.37 - 2.33 (m, 1H), 2.27 - 2.24 (m, 1H), 1.96 - 1.76 (m, 3H), 1.45 (s, 9H).

[0627] Preparation 12. tert-Butyl (lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.l]octane-8-carboxylate P12. Boc                             Boc < 4      1)ace-ci / k2co3 7^ S? F 2>MeOH * F I                                                     H Bn P11                              P12 A mixture of tert-butyl (lS,5S)-3-benzyl-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Pll, 900 mg, 90% purity, 2.23 mmol), potassium carbonate (30 mg, 0.22 mmol) ACE-CI (2.23 g, 15.6 mmol) in toluene (9 mL) was stirred and heated at 120°C overnight in inert atm, concentrated under reduced pressure. The residue was treated with MeOH (10 mL), the resulted mixture was filtered, the filtrate was stirred at 60°C for 2 h and concentrated. The residue was dissolved in H2O (10 mL) and the solution was washed with petroleum ether (2x10 mL). The aqueous layer was neutralized with sat. aq. solution of NaHCCL and extracted with DCM (3x10 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered and concentrated under reduced pressure to afford the title compound P12 (370 mg, 90% purity by 'H NMR, 40% yield) as a colorless oil. 'H NMR (400 MHz, CDCh), 8: 4.94 - 4.86 (m, 1H), 4.13 (d, . / = 5.2 Hz, 1H), 3.14 (d, . / = 12.8 Hz, 1H), 2.96 (d, J= 12.4 Hz, 1H), 2.71 (d, J= 12.8 Hz, 1H), 2.54 (d, J= 12.8 Hz, 1H), 2.21 -2.17(m, 1H), 1.99- 1.91 (m, 2H), 1.69 - 1.65 (m, 1H), 1.41 (m, 3H).

[0628] Preparation 13. tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P13. BOC I PI                                                        P13 A solution of DIPEA (6.32 g, 48.9 mmol) in DCM (20 mL) was added dropwise to a stirred mixture of tert-butyl l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Pl, 5.0 g, 90% purity, 16.3 mmol) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (4.94 g, 19.6 mmol) in DCM (100 mL) at -40°C. The reaction mixture was allowed to warm to ambient temperature, stirred at 20°C for 16 h, quenched with water (200 mL), and extracted with DCM (3x200 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a mixture of hexanes and EtOAc (0 to 20%) to afford the title compound P13 (7.0 g, 90% purity by 1H NMR, 78.5% yield) as a white solid. 'H NMR (400 MHz, CDC13), 8: 8.87 (s, 1H), 5.07 (dd, J= 28.2, 3.6 Hz, 1H), 4.70 - 4.33 (m, 3H), 3.80 (dd, J= 68.8, 12.6 Hz, 2H), 2.22 - 1.93 (m, 3H), 1.70 - 1.57 (m, 1H), 1.53 (s, 9H).

[0629] Preparation 14. tert-Butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate P14. A mixture of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P13, 7.0 g, 90% purity, 12.8 mmol), ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (6.11 g, 38.5 mmol), DIPEA (6.62 g, 51.2 mmol) and 1,4-dioxane (120 mL) was stirred at 90°C for 16 h, quenched with water (200 mL), and extracted with EtOAc (3x200 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a mixture of hexanes and EtOAc (1:1) to give the title compound P14 (7.5 g, 90% purity by 'H NMR, 85.9% yield) as a white solid. 'H NMR (400 MHz, CDC13), 8: 8.74 (s, 1H), 5.33 - 5.06 (m, 2H), 4.59 (dd, J= 12.4, 8.7 Hz, 1H), 4.45 - 4.40 (m, 2H), 4.28 - 4.16 (m, 2H), 3.82 - 3.62 (m, 2H), 3.45 - 2.89 (m, 4H), 2.28 - 1.88 (m, 9H), 1.65 - 1.58 (m, 1H), 1.53 (s, 9H).

[0630] Preparation 15. tert-Butyl l-(2,2-difluorovinyl)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.l]octane-8-carboxylate P15. Boc I F               OMOM A degassed mixture of / c / 7-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P14, 290 mg, 83.4% purity, 394.5 pmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-l-yl)ethynyl)triisopropylsilane (303.3 mg, 591.8 pmol), cataCXium A-Pd G3 (28.7 mg, 39.5 pmol), K3PO4 (251.2 mg, 1.18 mmol), 1,4-dioxane (6 mL), and water (1.5 mL) was stirred in nitrogen atm at 100°C for 3 h, cooled to ambient temperature, poured into water (10 mL), and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, fdtered and concentrated. The residue was purified by silica gel column chromatography with a mixture of hexanes and EtOAc (1:1) to afford 290 mg (69%) of the title compound P15 (90% purity) as a yellow solid. LCMS: Rt= 1.581 min; (ESI) calc, for CsifWs^OsSi [M+H]+ 963.5, found 964.5. 1HNMR(400MHz, CDCE), 5: 9.09 (s, 1H), 7.80 - 7.77 (m, 1H), 7.51 (s, 1H), 7.37-7.34 (m, 1H), 7.31 - 7.26 (m, 1H), 5.59 - 5.23 (m, 3H), 5.19 - 5.04 (m, 1H), 5.00 - 4.49 (m, 3H), 4.46 - 4.18 (m, 2H), 4.10 - 3.95 (m, 1H), 3.88 - 3.56 (m, 1H), 3.51 (s, 3H), 3.49 - 3.41 (m, 1H), 3.31 - 3.11 (m, 1H), 2.72 - 2.31 (m, 3H), 2.28 - 2.15 (m, 3H), 2.11-1.93 (m, 3H), 1.87 - 1.60 (m, 3H), 1.52 (s, 9H), 0.87 - 0.83 (m, 18H), 0.58 -0.46 (m, 3H).

[0631] Preparation 16. 4-(4-(1-(2,2-Difluorovinyl)-3,8-diazabicyclo[3.2. l]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5 -((trii sopropyl silyl)ethynyl)naphthalen-2-ol P16. To a stirred solution of tert-butyl l-(2,2-difluorovinyl)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P15, 290 mg, 90% purity, 0.27 mmol) in DCM (3 mL) was added 4M solution of HC1 in 1,4-dioxane (3 mL, 6.0 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 2 h and concentrated to afford 250 mg (97%) of the title compound P16 (86.4% purity by LCMS) as a yellow solid that was used for the next step without further purification. LCMS: Rt = 1.086 min; (ESI) calc, for C44H5iF5N6O2Si [M+H]+ 819.4, found 819.4.

[0632] Preparation 17. tert-Butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.l]octane-8-carboxylate P17. A degassed suspension of tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane -8-carb oxy late (P14, 500 mg, 90% purity, 734.0 pmol), tertbutyl (3-cyano-4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (593.5 mg, 1.47 mmol), Xphos Pd G3 (124.3 mg, 146.8 pmol), Xphos (139.8 mg, 293.6 pmol), and K3PO4 (467.4 mg, 2.20 mmol) in toluene (10 mL) was stirred at 100°C for 6 h in inert atm, poured into water (10 mL), and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with a mixture of hexanes and EtOAc (1:1) to give the title compound P17 (180 mg, 90% purity, 25.4% yield) as a yellow solid. LCMS: Rt= 1.463min; (ESI) calc, for C42H45F5N8O5S [M+H]+ 869.3, found 869.2.

[0633] Preparation 18. tert-Butyl l-(2,2-difluorovinyl)-3-(7-(5,6-dimethyl-l-(tetrahydro- 2H-pyran-2-yl)-lH-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.l]octane-8-carboxylate P18. A degassed suspension of fe / 7-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P14, 300 mg, 90% purity, 442.4 pmol), 5,6-dimethyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-IH-indazole (204 mg, 572.5 pmol), cataCXium A Pd G3 (32 mg, 44.0 pmol), and K3PO4 (280 mg, 1.32 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was stirred at 100°C for 3 h in inert atm, poured into water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, fdtered, and concentrated. The residue was purified by silica gel column chromatography with a mixture of hexanes and EtOAc (1:1) to give the title compound P18 (300 mg, 95.7% purity, 80.8% yield) as a yellow solid. LCMS: Rt = 1.404 min; (ESI) calc, for C42H50F4N8O4 [M+H]+ 807.4, found 807.3. 1HNMR(400 MHz, CDCI3), 5: 9.30 (s, 1H), 7.64 (s, 1H), 7.55 (d, J= 11.6 Hz, 1H), 5.75 - 5.71 (m, 1H), 5.52 (d, 7=52.4 Hz, 1H), 5.31 - 5.15 (m, 1H), 4.96 -4.66 (m, 2H), 4.62 - 4.34 (m, 3H), 4.23 - 3.98 (m, 3H), 3.93 - 3.71 (m, 3H), 3.63 - 3.55 (m, 1H), 3.37 - 3.27 (m, 1H), 2.85 - 2.66 (m, 1H), 2.58 - 2.50 (m, 5H), 2.46 - 2.40 (m, 1H), 2.37 -2.25 (m, 4H), 2.21 (s, 3H), 2.17-2.12 (m, 1H), 2.11 - 2.02 (m, 3H), 1.84- 1.61 (m, 4H), 1.54 (s, 9H).

[0634] Preparation 19. / e / V-Butyl 3-(7-Chloro-2-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.l]octane-8-carboxylate P19. A mixture of / e / V-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P13, 500 mg, 90% purity, 0.92 mmol), (S)-(2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (210 mg, 1.1 mmol), DIPEA (360 mg, 2.76 mmol), and 1,4-dioxane (6 mL) was stirred at 90°C for 36 h, quenched with water (10 mL), and extracted with EtOAc (3x10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with a mixture of hexanes and EtOAc (1:1) to afford the title compound P19 (320 mg, 90% purity by ’H NMR, 49% yield) as a yellow solid. 'H NMR (400 MHz, CDCh), 8: 8.75 (s, 1H), 5.17 - 5.09 (m, 1H), 4.63 - 4.33 (m, 5H), 3.82 - 3.49 (m, 5H), 2.96 - 2.82 (m, 1H), 2.19 -2.04 (m, 5H), 1.69 - 1.53 (m, 14H).

[0635] Preparation 20. ze / V-Butyl 3-(2-(((S)-2-(Difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.l]octane-8-carboxylate P20. OMOM A degassed mixture of tert-butyl 3-(7-Chloro-2-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (P19, 320 mg, 90% purity, 0.45 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triiso propylsilane (460 mg, 0.90 mmol), cataCXium A Pd G3 (40 mg, 0.05 mmol), K3PO4 (290 mg, 1.35 mmol), 1,4-dioxane (5 mL), and water (1 mL) was stirred at 100°C for 3 h in inert atm, poured into water (10 mL), and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was subjected to silica gel column chromatography with a mixture of hexanes and EtOAc (1:1) to afford the title compound P20 (350 mg, 90% purity by rH NMR, 70% yield) as a yellow solid. rH NMR (400 MHz, CDCI3), 5: 9.08 (s, 1H), 7.80 - 7.76 (m, 1H), 7.51 (d, J= 2.4 Hz, 1H), 7.34 - 7.29 (m, 2H), 5.32 - 5.27 (m, 2H), 5.15 - 5.08 (m, 1H), 4.91 - 4.78 (m, 1H), 4.48 - 4.42 (m, 1H), 4.27 -3.57 (m, 5H), 3.51 (s, 3H), 3.41 - 3.20 (m, 2H), 2.82 - 2.45 (m, 3H), 1.95 - 1.92 (m, 8H), 1.53 (s, 10H), 0.88 - 0.84 (m, 18H), 0.56 - 0.49 (m, 3H).

[0636] Preparation 21. tert-Butyl 3-(7-chloro-2-(((R)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2. l]octane-8-carboxylate P21. A mixture of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P13, 500 mg, 90% purity, 0.92 mmol), (R)-(2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (208.4 mg, 1.10 mmol), DIPEA (355.9 mg, 2.75 mmol) and l,4-dioxane(5 mL) was stirred at 90°C for 24 h, diluted with water (20 mL), and extracted with EtOAc (3x20 mL). Combined organic layers were washed with brine, dried over anh. Na2SO4. filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography with a mixture of hexanes and EtOAc (0 to 50%) to give the title compound P21 (280 mg, 89.3% purity by LCMS, 42.4% yield) as a white solid. LCMS: Rt = 1.402 min; (ESI) calc, for C29H32CIF5N6O3 [M+H]+ 643.2, found 643.2.

[0637] Preparation 22. tert-Butyl 3-(2-(((R)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P22. OMOM A suspension of tert-butyl 3-(7-chloro-2-(((R)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P21, 280 mg, 89.3% purity, 388.8 pmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (303.3 mg, 544.4 pmol), cataCXium APd G3 (28.3 mg, 38.9 pmol) and K3PO4 (247.6 mg, 1.17 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was flashed with nitrogen, stirred at 100°C in nitrogen atm for 3 h, poured into water (10 mL), and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over anh. NazSCh, filtered and concentrated. The residue was subjected to silica gel flash chromatography with EtOAc in hexanes (0 to 50%) to give the title compound P22 (240 mg, 100% purity, 62.2% yield) as a yellow solid. LCMS: Rt = 1.670 min; (ESI) [M+H]+ calc, for C52H62F6N6O5Si 993.5, found 993.3.

[0638] Preparation 23. 4-(2-(((R)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol P23 To a solution of tert-butyl 3-(2-(((R)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P22, 290 mg, 0.27 mmol) in DCM (4 mL) was added 4 M solution of HC1 in 1,4-dioxane (2 mL, 4.0 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 2 h. The mixture was concentrated to afford the crude product P23 (280 mg, 88.3% purity by LCMS, HC1 salt, 100% yield) as yellow solid that was used for the next step without further purification. LCMS: Rt = 1.359 min; (ESI) calc, for C45H5oF6N602Si [M+H]+ 849.4, found 849.3.

[0639] Preparation 24. Methyl 2-methylene-5-oxotetrahydro-lH-pyrrolizine-7a(5H)-carb oxy late P24. LHMDS (IM solution in THF, 734 mL, 0.734 mol) was added dropwise to a stirred solution of methyl 5-oxopyrrolidine-2-carboxylate (50.0 g, 100% purity, 0.349 mol) and 3-chloro-2-(chloromethyl)prop-l-ene (144.0 g, 1.15 mol) in THF (500 mL) at -40°C under nitrogen atm. The resulting mixture was stirred at 25°C for 16 h, quenched by the addition of sat. aq. solution of NH4C1 (100 ml) at 0°C, neutralized to pH = 7 with IM aq. solution of HC1, and extracted with EtOAc (3x200 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a mixture of hexanes and EtOAc (5 to 50%) to afford the title compound P24 (23.0 g, 86% purity by LCMS, 29% yield) as a colorless oil. LCMS: Rt= 1.059 min; (ESI) calc, for C10H13NO3 [M+H]+ 196.1, found 196.1. 'HNMR (400 MHz, DMSO-t / 6), 8: 5.06 - 5.01 (m, 2H), 4.18 - 4.08 (m, 1H), 3.67 (s, 3H), 3.59 - 3.33 (m, 1H), 2.93 - 2.89 (m, 1H), 2.64 - 2.56 (m, 2H), 2.44 - 2.20 (m, 3H).

[0640] Preparation 25. 7a-(Hydroxymethyl)-6-methylenehexahydro-3H-pyrrolizin-3-one P25 A mixture of methyl 2-methylene-5-oxotetrahydro-lH-pyrrolizine-7a(5H)-carboxylate (P24, 2.0 g, 86% purity, 8.81 mmol), NaBH4 (667 mg, 17.62 mmol), and THF (20 mL) was stirred at 25°C for 12 h, quenched with MeOH (10 ml), diluted with water, and extracted with EtOAc (3x20 mL). The combined organic layers were dried with anh. Na2SO4, fdtered, and concentrated under reduced pressure to afford the title compound P25 (1.4 g, 90% purity by ’HNMR, 86% yield) as a colorless oil. LCMS: Rt = 0.861 min; (ESI) calc, for C9H13NO2 [M+H]+ 168.1, found 168.1. NMR (400 MHz, DMS04), 8: 5.03 -4.98 (m, 2H), 4.07 - 4.03 (m, 1H), 3.60 - 3.49 (m, 1H), 3.26 - 3.24 (s, 2H), 2.65 - 2.53 (m, 2H), 2.29-2.15 (m, 3H), 1.90 - 1.82 (m, 1H).

[0641] Preparation          26.           7a-((( / erLButyldimethylsilyl)oxy)methyl)-6- methylenehexahydro-3H-pyrrolizin-3-one P26. P25 O                       P26 O NaH (753 mg, 18.84 mmol) was added to a stirred solution of 7a-(hydroxymethyl)-6-methylenehexahydro-3H-pyrrolizin-3-one (P25, 1.4 g, 90% purity, 7.54 mmol) in THF (20 mL). The mixture was stirred at 0°C for 1 h, and then TBSC1 (1.7 g, 11.30 mmol) was added. The resulted mixture was stirred at 25°C for 1 h, quenched with H2O (10 mL), and extracted with EtOAc (3x20 mL). The combined organic layers were dried with anh. Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a mixture of hexanes and EtOAc (5 to 50%) to afford the title compound P26 (1.7 g, 90% purity by 'H NMR, 72% yield) as a colorless oil. LCMS: Rt = 1.575 min; (ESI) calc, for Ci5H27NO2Si [M+H]+282.2, found 282.1. XHNMR (400 MHz, DMSO-6 / 6), 8: 5.01 - 4.98 (m, 2H), 4.08 - 4.04 (m, 1H), 3.53 - 3.42 (m, 3H), 2.67 - 2.51 (m, 2H), 2.37 - 2.33 (m, 1H), 2.30 - 2.08 (m, 2H), 1.99 - 1.87 (m, 1H), 0.87 (s, 9H), 0.03 - 0.02 (m, 6H).

[0642] Preparation          27.          7a'-(((to7-Butyldimethylsilyl)oxy)methyl)-6'- methylenehexahydrospiro[cyclopropane-l,3'-pyrrolizine] P27. EtMgBr (22 ml, 1 M, 21.74 mmol) was added dropwise to a stirred solution of TTIP (1.78 g, 10.87 mmol) in THF (20 ml) at -78°C under nitrogen atm. The mixture was stirred for 30 min, then a solution of 7a-(((terLbutyldimethylsilyl)oxy)methyl)-6-methylenehexahydro-3H-pyrrolizin-3-one (P26, 1.7 g, 90% purity, 5.44 mmol) in THF (10 mL) was added. The mixture was stirred at 25°C for 2 h, quenched with H2O (10 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were dried with anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a mixture of hexanes and EtOAc (5 to 50%) to afford the title compound P27 (570 mg, 80% purity by 1H NMR, 29% yield) as a white solid. LC-MS: Rt = 1.367 min; (ESI) calc, for CnHuNOSi [M+H]+ 294.2, found 294.2. 'H NMR (400 MHz, DMSO-t / 6), 5: 4.82 (s, 2H), 3.39 - 3.27 (m, 3H), 2.44 - 2.29 (m, 2H), 2.13 - 2.05 (m, 1H), 1.92 - 1.84 (m, 1H), 1.72 - 1.66 (m, 1H), 1.35 - 1.23 (m, 2H), 0.87 (s, 9H), 0.75 -0.69 (m, 1H), 0.54 - 0.49 (m, 1H), 0.41 - 0.29 (m, 2H), 0.02 - 0.01 (m, 6H).

[0643] Preparation 28. (6'-Methylenetetrahydrospiro[cyclopropane-l,3'-pyrrolizin]-7a'(5'H)-yl)methanol P28. To a solution of 7a'-((( / erLbutyldimethylsilyl)oxy)methyl)-6'-methylenehexahydrospiro[cyclopropane-l,3'-pyrrolizine] (P27, 570 mg, 90% purity, 1.75 mmol) in MeOH (5 mL) was added dropwise IM solution of HC1 in dioxane (5 ml) at 0°C. The reaction mixture was stirred at 25°C for 2 h, concentrated under reduced pressure without heating to afford the title compound P28 (414 mg, 80% purity by 'H NMR, 93% yield) as a yellow solid that was used directly for the next step. LCMS: Rt = 0.619 min; (ESI) calc, for C11H17NO [M+H]+ 180.1, found 180.1. 'HNMR (400 MHz, DMSO-J6), 8: 4.82-4.81 (m, 2H), 4.33 (m, 1H), 3.41 - 3.38 (m, 1H), 3.23 - 3.16 (m, 2H), 2.58 - 2.51 (m, 1H), 2.32 - 2.28 (m, 1H), 2.15 - 2.08 (m, 1H), 1.92 - 1.85 (m, 1H), 1.70 - 1.64 (m, 1H), 1.37 - 1.26 (m, 2H), 0.72 - 0.53 (m, 1H), 0.50 - 0.43 (m, 2H), 0.33 - 0.29 (m, 1H).

[0644] Preparation         29.         tert-Butyl         3-(7-chloro-8-fluoro-2-((6'- methylenetetrahydrospiro[cyclopropane-l,3'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P29. NaH (130 mg, 3.23 mmol) was added to a solution of (6'-methylenetetrahydrospiro[cyclopropane-l,3'-pyrrolizin]-7a'(5'H)-yl)methanol (P28, 414 mg, 80% purity, 1.62 mmol) in THF (5 mL) at 0°C. The mixture was stirred for 30 min, then tert-butyl        3-(2,7-di chi oro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P13, 898 mg, 90% purity, 1.65 mmol) was added. The mixture was stirred at 25°C for 2 h, quenched with H2O (10 ml), and extracted with EtOAc (3x20 mL). The combined organic layers were dried over anh. Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a mixture of hexanes and EtOAc (10 to 50%) to afford the title compound P29 (540 mg, 90% purity by LCMS, 47% yield) as a yellow solid. LCMS: Rt = 1.407 min; (ESI) calc, for C31H36CIF3N6O3 [M+H]’ 633.3, found 633.2. 'H NMR (400 MHz, DMSO-t / 6), 8: 8.95 (s, 1H), 5.24 - 5.17 (m, 1H), 4.88 - 4.87 (m, 2H), 4.69 - 4.67 (m, 1H), 4.35 - 4.24 (m, 3H), 4.18 - 4.14 (m, 1H), 3.78 - 3.70 (m, 2H), 3.48 -3.37 (m, 2H), 2.68 - 2.61 (m, 2H), 2.20 - 1.87 (m, 7H), 1.47 (s, 9H), 1.43 - 1.38 (m, 1H), 0.79 - 0.74 (m, 1H), 0.59 - 0.35 (m, 3H).

[0645] Preparation         30.         l-(2,2-difluorovinyl)-3-(8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-((6'- methylenetetrahydrospiro[cyclopropane-l,3'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P30. A degassed mixture of tert-butyl 3-(7-chloro-8-fluoro-2-((6'-methylenetetrahydrospiro[cyclopropane-l,3'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P29, 400 mg, 90% purity, 586.62 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (800 mg, 2.08 mmol), K3PO4 (400 mg, 1.89 mmol), cataCXium A-Pd G3 (160 mg, 1.51 mmol), THF (36 mL), and H2O (6 mL) was flashed with nitrogen, stirred at 60°C for 3 h, diluted with water (10 mL), and extracted with EtOAc (3x20 mL). The combined organic layers were dried with anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a mixture of hexanes and EtOAc (10 to 50%) to afford the title compound P30 (344 mg, 90% purity by LCMS, 55% yield) as a yellow solid. LCMS: Rt = 1.681 min; (ESI) calc, for C54H66F4N6OsSi [M+H]+ 983.5, found 983.4.

[0646] Preparation 31. 4-(4-(1-(2,2-Difluorovinyl)-3,8-diazabicyclo[3.2. l]octan-3-yl)-8-fluoro-2-((6'-methylenetetrahydrospiro[cyclopropane-l,3'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5- ((trii sopropyl silyl)ethynyl )naphthalen-2-ol P31. To a solution of tert-butyl l-(2,2-difluorovinyl)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-((6'- methylenetetrahydrospiro[cyclopropane-l,3'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P30, 344 mg, 90% purity, 0.315 mmol) in DCM (10 mL) was added slowly 4M solution of HC1 in dioxane (5 mL) at 0°C (2 mL). The reaction mixture was stirred at 0°C for 1 h, concentrated under reduced pressure without heating to afford the title compound P31 (280 mg, 90% purity by LCMS, 95% yield) as a yellow solid that was used for the next step without additional purification. LCMS: Rt = 1.370 min; (ESI) calc, for C47H54F4N6O2Si [M+H]+ 839.4, found 839.3.

[0647] Preparation 32. 7-Bromo-2-chloro-8-fluoro-6-iodo-4-(methylthio)quinazoline P32 F                        P32 F A solution (15.0 g, 213.4 mmol) of sodium thiomethoxide in water (60 mL) was added dropwise to a stirred solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (90.0 g, 213.4 mmol) in THF (900 mL) at 0°C. The reaction mixture was stirred at 25°C for 2 h. The formed precipitate was collected by filtration, washed with hexane (100 mL), and dried to afford the title compound P32 (75.0 g, 90% purity, 73.0% yield) as a white solid that was used for the next step without further purification. 1H NMR (400 MHz, CDCh), 8: 8.29 (s, 1H), 2.71 (s, 3H).

[0648] Preparation 33. 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6-iodo-4-(methylthio)quinazoline P33. A mixture of 7-bromo-2-chloro-8-fluoro-6-iodo-4-(methylthio)quinazoline (P32, 115.0 g, 90% purity, 239.5 mmol), ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (53.3 g, 335.4 mmol), DIPEA (92.7 g, 718.8 mmol) and ACN (1200 mL) was stirred at 100°C for 24 h. The precipitate was collected by filtration, washed with hexane (10 mL), and dried to afford the title compound P33 (90.0 g, 90% purity, 68.0% yield) as a yellow solid, 'HNMR (400 MHz, DMSO-t / 6), 8: 8.24 (s, 1H), 5.37 - 5.23 (m, 1H), 4.21 - 4.18 (m, 1H), 4.12 - 4.09 (m, 1H), 3.10 - 3.03 (m, 3H), 2.85 - 2.79 (m, 1H), 2.67 (s, 3H), 2.18 - 2.00 (m, 3H), 1.84 -1.75 (m, 3H).

[0649] Preparation 34. 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)-6-vinylquinazoline P34. A mixture of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6-iodo-4-(methylthio)quinazoline (P33, 3.3 g, 80% purity, 4.75 mmol), Pinacolvinylboronate (1.1 g, 7.12 mmol), K2CO3 (1.31 g, 9.49 mmol), Pd(dppf)Ch (174 mg, 0.238 mmol), 1,4-dioxane (50 mL) and water (5 mL) was degassed and purged with N2 for 3 times, stirred at 70°C for 6 h, diluted with water (10 mL), and extracted with EtOAc (3x20 mL). The combined organic layers were dried with anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography with EtOAc in hexanes (10 to 50%) (to afford the title compound P34 (1.8 g, 93.5% purity by LCMS, 77.7% yield) as a yellow solid. LC-MS: Rt = 1.329 min; (ESI) calc, for Ci9H2oBrF2N30S [M+H]+ 456.1, found 456.0.

[0650] Preparation 35. 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline-6-carbaldehyde P35. A mixture of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)-6-vinylquinazoline (P34, 900 mg, 93.5% purity, 1.84 mmol), NMMO (430 mg, 3.69 mmol) and K2OsO4 (61 mg, 184.4 pmol) in THF (15 mL) / H20 (5 ml) was stirred at 0°C for 1 h, then NaIO4 (1.1 g, 7.12 mmol) was added to the mixture. The resulted mixture was stirred at 25°C for 2 h. quenched with sat. aq. solution of Na2SO3 (20 mL), diluted with sat. aq. solution of NaHCOa (20 mL), and extracted with EtOAc (3x20 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with EtOAc in DCM (10 to 50%) to afford the title compound P35 (300 mg, 84.6% purity by LCMS, 30.0% yield) as a yellow solid. LCMS: Rt = 1.218 min; (ESI) calc, for Ci8Hi8BrF2N3O2S [M+H]+ 458.0, found 458.0.

[0651] Preparation 36. 7-Bromo-6-(difluoromethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline P36. DAST (268 mg, 1.66 mmol) was added drop-wise a stirred solution of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline-6-carbaldehyde (P35, 300 mg, 84.6% purity, 0.55 mmol) in DCE (5 mL) at 0°C under atm N2. The reaction mixture was stirred at 50°C stirred for 4 h diluted with water (10 ml), cooled to 0°C, quenched with sat. aq. solution of NaHCCh (10 ml), and extracted with DCM (3x20 ml). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography with EtOAc in DCM (10 to 50%) to afford the title compound P36 (210 mg, 93.2% purity by LCMS, 73.5% yield) as a yellow solid. LCMS: Rt= 1.288 min; (ESI) calc, for CisHisB^NaOS [M+H]+ 480.0, found 480.0. 'H NMR (400 MHz, CDCI3), 5: 8.08 (s, 1H), 6.95 (t, J= 54.4 Hz, 1H), 5.43 - 5.30 (m, 1H), 4.62 - 4.40 (m, 2H), 3.73 - 3.23 (m, 3H), 3.15 - 3.01 (m, 1H), 2.73 (s, 3H), 2.51 - 2.18 (m, 3H), 2.14- 1.96 (m, 3H).

[0652] Preparation 37. tert-Butyl (3-cyano-4-(6-(difluoromethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)quinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate P37. F A degassed mixture of 7-bromo-6-(difluoromethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline (P36, 210 mg, 93.2% purity, 407 pmol), to7-butyl (3-cyano-4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (329 mg, 814 pmol), DPEphosPdCh (58 mg, 81.5 pmol), CS2CO3 (398 mg, 1.22 mmol) and 1,4-dioxane (6 mL) was stirred under nitrogen atm at 105°C for 4 h, poured into water (10 mL), and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over Na2SO4, fdtered, and concentrated. The residue was purified by silica gel flash chromatography with EtOAc in DCM (10 to 50%) to afford the title compound P37 (120 mg, 89.6% purity, 38.2% yield) as a yellow solid. LCMS: Rt = 1.465 min; (ESI) calc, for C32H30F5N5O3S2 [M+H]+ 692.2, found 692.1.

[0653] Preparation 38. to7-Butyl (4-(4-chloro-6-(difluoromethyl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7- fluorobenzo[b]thiophen-2-yl)carbamate P38. To a solution of tert-butyl (3-cyano-4-(6-(difluoromethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1 H-py rrolizin-7a(5H)-yl)m ethoxy )-4-(methy lthio)quinazolin-7-y 1)-7-fluorobenzo[b] thiophen-2-yl)carbamate (P37, 120 mg, 89.6% purity, 0.15 mmol) in DCM (10 mL) at 0°C was added SO2CI2 (63 mg, 0.47 mmol) in DCM (3 mL) slowly. The reaction mixture was stirred at 0°C for 0.5 h, concentrated under reduced pressure without heating to afford the title compound P38 (120 mg, 86.6% purity by LCMS, 98.3% yield) as a yellow solid that was used directly for the next step. LCMS: Rt = 1.447 min; (ESI) calc, for C31H27CIF5N5O3S [M+H]+ 680.1, found 680.0.

[0654] Preparation 39. tert-Butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-(difluoromethyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P39. A mixture of tert-butyl (4-(4-chloro-6-(difluoromethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7- fluorobenzo[b]thiophen-2-yl)carbamate (P38, 120 mg, 86.6% purity, 0.15 mmol), tertbutyl l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (78.6 mg, 80% purity, 0.23 mmol), DIPEA (98.8 mg, 0.76 mmol) and ACN (5 mL) was stirred at ambient temperature for 16 h, poured to water (10 mL), extracted with EtOAc (3x10 mL). The combined organic layers were dried with anh. Na2SO4, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel flash chromatography with EtOAc in hexanes (10 to 50%) to afford the title compound P39 (80 mg, 98.0% purity by LCMS, 55.9% yield) as a yellow solid. LCMS: Rt = 1.544 min; (ESI) calc, for C44H46F7N7O5 [M+H]+ 918.3, found 918.2. 'HNMR (400 MHz, CDCI3), 5: 7.96 (d, J= 6.0 Hz, 1H), 7.35 -7.29 (m, 1H), 7.15 (t, .7= 8.4 Hz, 1H), 6.31 (t, J= 55.2 Hz, 1H), 5.41-5.28 (m, 1H), 5.16 - 5.09 (m, 1H), 4.68 - 4.55 (m, 1H), 4.42 - 4.32 (m, 3H), 3.82 - 3.75 (m, 1H), 3.70 - 3.62 (m, 1H), 3.49 - 3.18 (m, 2H), 3.13 - 2.98 (m, 1H), 2.53 - 2.16 (m, 4H), 2.04 -1.97 (m, 3H), 1.79-1.61 (m, 4H), 1.54 (s, 9H), 1.53 (s, 9H).

[0655] Preparation 40. 7-Bromo-2,6-dichloro-8-fluoro-4-(methylthio)quinazoline P40. A solution of sodium thiomethoxide (2.33 g, 33.30 mmol) in water (20 mL) was added dropwise to a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (10.0 g, 100% purity, 30.27 mmol) in THF (100 mL) at 0°C. The reaction mixture was stirred at 25°C for 2 h. The precipitate was collected by filtration and washed with hexane (10 mL) to afford the title compound P40 (8.0 g, 90% purity by 'H NMR, 70% yield) as a white solid. 'H NMR (400 MHz, DMSO-de), 8: 8.19 (s, 1H), 2.73 (s, 3H).

[0656] Preparation 41. 7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline P41. A mixture of 7-bromo-2,6-dichloro-8-fluoro-4-(methylthio) (P40, 8.0 g, 90% purity, 21.05 mmol), ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (5.03 g, 31.58 mmol) and DIPEA (10.88 g, 84.21 mmol) in ACN (80 mL) was stirred at 80°C for 12 h. The precipitate was collected by filtration and washed with hexane (10 mL) to afford the title compound P41 (6.0 g, 80% purity by 'H NMR, 49% yield) as a yellow solid. LCMS: Rt = 1.077 min; (ESI) calc, for Ci7Hi7BrClF2N3OS [M+H]+ 464.0, found 464.0. XHNMR (400 MHz, CDC13), 8: 8.02 - 7.91 (m, 1H), 5.39 - 4.26 (m, 1H), 4.41 - 4.33 (m, 2H), 3.41 - 3.21 (m, 3H), 3.05 - 3.00 (m, 1H), 2.72 (s, 3H), 2.34 - 2.18 (m, 3H), 2.02 - 1.98 (m, 3H).

[0657] Preparation 42. / c / v-Butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)quinazolin-7-yl)-3-cyano-7- fluorobenzo[b]thiophen-2-yl)carbamate P42. A degassed mixture of 7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline (P41, 3.0 g, 80% purity, 5.16 mmol),         te / 7-butyl         (3-cyano-4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-7- fluorobenzo[b]thiophen-2-yl)carbamate (4.18 g, 10.33 mmol), K3PO4 (5.48 g, 25.82 mmol), Pd2(dba)3 (473 mg, 0.516 mmol) and (R)-MOP (484 mg, 1.05 mmol), and 1,4-dioxane (30 mL) was stirred at 80°C for 2 h, diluted with water (10 mL), and extracted with EtOAc (3x20 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with EtOAc in hexanes (10 to 50%) to afford the title compound P42 (2.8 g, 85% purity by LCMS, 75% yield) as a yellow solid. LCMS: Rt = 1.400 min; (ESI) calc, for C31H29CIF3N5O3S2 [M+H]+ 676.1, found 676.1.

[0658] Preparation 43. tert-Butyl (3-cyano-4-(4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate P43. A solution of SO2CI2 (254 mg, 1.89 mmol) in DCM (2 mL) was added slowly to a solution of tert-butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (P42, 500 mg, 85% purity, 0.629 mmol) in DCM (10 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 h and concentrated under reduced pressure without heating to afford the title compound P43 (410 mg, 89% purity by LCMS, 87% yield) as a yellow solid. The crude product was used at the next step without further purification. LCMS: Rt = 1.397 min; (ESI) calc, for C30H26CI2F3N5O3S [M+H]+ 664.1, found 664.1.

[0659] Preparation 44. tert-Butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl )methoxy)quinazolin-4-yl)-1-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.l]octane-8-carboxylate P44. A mixture of tert-butyl l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (345 mg, 50% purity), tert-butyl (3-cyano-4-(4,6-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7- fluorobenzo[b]thiophen-2-yl)carbamate (P43, 410 mg, 89% purity, 0.549 mmol), DIPEA (213 mg, 1.65 mmol) and ACN (5 mL) was stirred at ambient temperature for 2 h, diluted with water (5 mL), and extracted with EtOAc (3x5 mL). The combined organic layers were dried over anh. Na2SO4, fdtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography with EtOAc in hexanes (10 to 50%) to afford the title compound P44 (160 mg, 80% purity by LCMS, 26% yield) as a yellow solid. LCMS: Rt = 1.586 min; (ESI) calc, for C43H45CIF5N7O5S [M+H]+ 902.3, found 902.2.

[0660] Preparation 45. (S)-7-Bromo-6-chloro-2-((2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-4-(methylthio)quinazoline P45. A mixture of 7-bromo-2,6-dichloro-8-fluoro-4-(methylthio) (P40, 1.1g, 90% purity, 2.91 mmol), (S)-(2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (500 mg, 2.64 mmol), DIPEA (1.02 g, 7.93 mmol) and 1,4-dioxane (10 mL) was stirred at 100°C for 2 days and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography with EtOAc in hexanes (10 to 50%) to afford the title compound P45 (600 mg, 90% purity by LCMS, 41% yield) as a yellow solid. LCMS: Rt = 1.317 min; (ESI) calc, for Ci8Hi6BrClF3N3OS [M+H]+ 494.0, found 493.9. 'H NMR (400 MHz, DMSO-t / 6), 8: 8.06 - 8.05 (m, 1H), 4.26 - 4.17 (m, 2H), 3.68 - 3.64 (m, 1H), 3.36 - 3.34 (m, 1H), 3.03 - 2.98 (m, 1H), 2.69 (s, 3H), 2.68 - 2.55 (m,3H), 2.03 - 1.76 (m, 4H).

[0661] Preparation 46. tert-Butyl (4-(6-chloro-2-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-4-(methylthio)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate P46. A degassed mixture of (S)-7-bromo-6-chloro-2-((2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-4-(methylthio)quinazoline (P45, 600 mg, 90% purity, 1.09 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl) carbamate (882 mg, 2.18 mmol), K3PO4 (695 mg, 3.27 mmol), Pd2(dba)3 (100 mg, 0.109 mmol), (R)-MOP (100 mg, 0.218 mmol) in 1,4-dioxane (10 mL) was stirred at 80°C for 2 h in inert atm, diluted with water (10 mL), and extracted with EtOAc (3x20 mL). The combined organic layers were dried with anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with EtOAc in hexanes (10 to 50%) to afford the title compound P46 (600 mg, 90% purity by LCMS, 70% yield) as a yellow solid. LCMS: Rt = 1.451 min; (ESI) calc, for C32H28CIF4N5O3S2 [M+H]+ 706.1, found 706.0.

[0662] Preparation 47. tert-Butyl (3-cyano-4-(4,6-dichloro-2-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7- yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate P47. A solution of SO2CI2 (310 mg, 2.29 mmol) in DCM (2 mL) was slowly added to a cooled to 0°C solution of / c / 7-butyl (4-(6-chloro-2-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-4-(methylthio)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (P46, 600 mg, 90% purity, 0.765 mmol) in DCM (10 mL) at. The reaction mixture was stirred at 0°C for 1 h and concentrated under reduced pressure without heating to afford the title compound P47 (550 mg, 90% purity by LCMS, 93% yield) as a yellow solid. The crude product was used directly for the next step. LCMS: Rt = 1.437 min; (ESI) calc, for C31H25CI2F4N5O3S [M+H]+ 694.1, found 694.0.

[0663] Preparation 48. / c / 7-Butyl 3-(7-(2-(( / c / 7-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-2-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.l]octane-8-carboxylate P48. To a solution of tert-butyl (3-cyano-4-(4,6-dichloro-2-(((S)-2- (difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7- yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (P47, 550 mg, 90% purity, 0.713 mmol) in ACN (5 mL) was added DIPEA (460 mg, 3.56 mmol) and tert-butyl l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (304 mg, 90% purity, 0.998 mmol). Then the mixture was stirred at ambient temperature for 2 h, diluted with water (5 mL), and extracted with EtOAc (3x5 mL). The combined organic layers were dried over anh. NazSO4, filtered, and concentrated under reduced pressure. The mixture was subjected to silica gel flash chromatography with EtOAc in hexanes (10 to 50%) to afford the title compound P48 (540 mg, 90% purity by LCMS, 73% yield) as a yellow solid. LCMS: Rt = 1.513 min; (ESI) calc, for C44H44CIF6N7O5S [M+H]+ 932.3, found 932.2.

[0664] Preparation         49. 7-Bromo-2-chloro-8-fluoro-4-(methylthi 0)-6- (trifluoromethyl)quinazoline P49. To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (5.0 g, 100% purity, 13.74 mmol) in THF (50 mL) at 0°C was added sodium thiomethoxide (1.0 g, 14.43 mmol) in water (15 mL). The reaction was stirred at 0°C for 2 h. The precipitate was collected by fdtration and washed with hexane (10 mL) to afford the title compound P49 (4.6 g, 98% purity by LCMS, 87% yield) as a white solid. LCMS: Rt = 1.685 min; (ESI) calc, for CioH4BrClF4N2S [M+H]+ 374. 9, found 374.9.

[0665] Preparation 50. 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)-6-(trifluoromethyl)quinazoline P50. A mixture of 7-bromo-2-chloro-8-fluoro-4-(methylthio)-6-(trifluoromethyl)quinazoline (P49, 4.3 g, 98% purity, 11.22 mmol), ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)m ethanol (2.68 g, 16.83 mmol) and DIPEA (4.35 g, 33.66 mmol) in ACN (50 mL) was stirred at 50°C for 12 h and cooled. The precipitate was collected by filtration and washed with hexane (10 mL) to afford the title compound P50 (3.9 g, 86% purity by LCMS, 60% yield) as a yellow solid. LCMS: Rt = 1.131 min; (ESI) calc, for Ci8Hi7BrF5N3OS [M+H]+ 498.0, found 498.0.

[0666] Preparation 51. 7-Bromo-4-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazoline P51. A solution of SO2CI2 (582 mg, 4.31 mmol) in DCM (5 mL) was added slowly to a stirred solution of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-4-(methylthio)-6-(trifluoromethyl)quinazoline (P50, 1.0 g, 86% purity, 1.73 mmol) in DCM (10 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 h and concentrated under reduced pressure without heating to afford the title compound P51 (1.0 g, 55% purity by LCMS, 55% yield) as a yellow solid. The crude product was used directly for the next step. LCMS: Rt = 1.084 min; (ESI) calc, for CnHuBrClFsNsO [M+H]+ 486.0, found 486.0.

[0667] Preparation 52. te / 7-Butyl 3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6-(tri fluoromethyl)quinazolin-4-yl)-1-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P52. To a stirred solution of 7-bromo-4-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazoline (P51, 410 mg, 89% purity, 0.549 mmol) in ACN (5 mL) was added DIPEA (292 mg, 2.26 mmol) and tert-butyl 1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (413 mg, 90% purity). The reaction mixture was stirred at ambient temperature for 2 h, diluted with water (5 mL), and extracted with EtOAc (3x5 mL). The combined organic layers were dried over anh. Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with EtOAc in hexanes (10 to 50%) to afford the title compound P52 (800 mg, 75% purity by LCMS, 73% yield) as a yellow solid. LCMS: Rt = 1.303 min; (ESI) calc, for CsoHisBiFtNsOi [M+H]+ 724.2, found 724.2.

[0668] Preparation 53. tert-Butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.l]octane-8-carboxylate P53. A degassed mixture of / ert-butyl 3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P52, 400 mg, 75% purity, 0.414 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (335 mg, 0.828 mmol), K3PO4 (264 mg, 1.24 mmol), Pd2(dba)s (80 mg, 0.083 mmol) and (R)-MOP (78 mg, 0.165 mmol) in 1,4-dioxane (16 mL) was stirred in inert atm at 100°C for 12 h, diluted with water (10 mL), and extracted with EtOAc (3x20 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography with EtOAc in hexanes (10 to 50%) to afford the title compound P53 (319 mg, 70% purity by LCMS, 58% yield) as a yellow solid. LCMS: Rt = 1.591 min; (ESI) calc, for C44H45F8N7O5S [M+H]+ 936.3, found 936.2.

[0669] Preparation 54 7-Bromo-4-(tert-butoxy)-2,6-dichloro-8-fluoroquinazoline P54. To a mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (5.0 g, 15.14 mmol) in THF (50 mL) was added IM solution of t-BuOLi (19.7 mL, 19.7 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 3 h, quenched with sat. aq. solution of NH4CI (30 mL), extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with a mixture of Hexanes and EtOAc (1:1) to afford the title compound P54 (4.3 g, 90% purity by 'H NMR, 70% yield) as a yellow solid. 'H NMR (400 MHz, CDCI3), 5: 7.97 (d, J = 2.0 Hz, 1H), 1.76 (s, 9H).

[0670] Preparation 55. 7-Bromo-4-( / erLbutoxy)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1 H-pyrrolizin-7a(5H)-yl)methoxy)quinazoline P55. A degassed mixture of 7-bromo-4-( / er / -butoxy)-2,6-dichloro-8-fluoroquinazoline (P54, 2.9 g, 90% purity, 7.09 mmol), ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (1.58 g, 9.93 mmol), RuPhos-Pd G2 (250 mg, 0.35 mmol), CS2CO3 (4.62 g, 14.2 mmol) and 1,4-dioxane (45 mL) stirred at 80°C for 16 h in inert atm, poured into water (30 mL), and extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes - EtOAc 1: 1) to give the title compound P55 (2.5 g, 90% purity by 'HNMR, 65% yield) as a yellow solid. LCMS: Rt = 1.346 min; (ESI) calc, for C20H23BrClF2N3O2 [M+H]+ 490.1, found 490.0. ’HNMR (400 MHz, CDCh), 5: 7.88 (d, J= 2.0 Hz, 1H), 5.38 - 5.25 (m, 1H), 4.29 (br. s, 2H), 3.37 - 3.22 (m, 3H), 3.02 -3.01 (m, 1H), 2.30 - 2.14 (m, 3H), 2.00 - 1.92 (m, 3H), 1.73 (s, 9H).

[0671] Preparation 56. 4-(te / 7-Butoxy)-6-Chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazoline P56. OMOM A degassed mixture of 7-Bromo-4-( / cr / -butoxy)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazoline (P55, 1.0 g, 90% purity, 1.83 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triiso- propylsilane (1.50 g, 2.93 mmol), BI-DIME (121 mg, 0.37 mmol), Pd(OAc)2 (40 mg, 0.18 mmol) and K3PO4 (1.16 g, 5.49 mmol) and 1,4-dioxane (20 mL) was stirred in inert atm at 100°C for 3 h, poured into water (15 mL), and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over anh. Na2SO4, fdtered, and concentrated. The residue was purified by silica gel column chromatography with a mixture of hexanes and EtOAc (2:1) to afford the title compound P56 (1.0 g, 90% purity by 'H NMR, 62% yield) as a yellow solid. LCMS: Rt = 1.650 min; (ESI) calc, for C43H53ClF3N3O4Si [M+H]+ 796.3, found 796.2. 'H NMR (400 MHz, CDC13), 8: 7.83 - 7.76 (m, 2H), 7.51 (d, J= 2.4 Hz, 1H), 7.30 - 7.28 (m, 1H), 7.09 -7.08 (m, 1H), 5.41 - 5.21 (m, 3H), 4.42 - 4.18 (m, 2H), 3.53 (s, 3H), 3.15 - 3.08 (m, 3H), 2.95 (br. s, 1H), 2.39 - 2.09 (m, 3H), 2.02 - 1.89 (m, 3H), 1.76 (s, 9H), 1.70 - 1.50 (m, 3H), 0.93 - 0.91 (m, 9H), 0.84 - 0.83 (m, 9H), 0.65 - 0.54 (m, 3H).

[0672] Preparation 57. 6-Chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol P57. OMOM A mixture of 4-(terM>utoxy)-6-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazoline (P56, 1.0 g, 90 % purity, 1.13 mmol) in ACN (16 mL), water (4 mL) and TFA (1 mL) was stirred for 2 h at 25°C and concentrated. The residue was subjected to HPLC purification to afford the title compound P57 (900 mg, 90% purity, 96% yield) as a yellow solid. LCMS: Rt = 1.411 min; (ESI) calc, for C39H45ClF3N3O4Si [M+H]+ 739.28, found 740.3. ’H NMR (400 MHz, CDCI3), 6: 8.02 -8.00 (m, 1H), 7.80 - 7.76 (m, 1H), 7.51 (d, J= 2.4 Hz, 1H), 7.31 - 7.29 (m, 1H), 7.09 - 7.08 (m, 1H), 5.41 - 5.22 (m, 3H), 4.43 - 4.24 (m, 2H), 3.52 (s, 3H), 3.49 - 3.41 (m, 1H), 3.39 - 3.24 (m, 2H), 3.11-3.03 (m, 1H), 2.32 - 2.08 (m, 4H), 2.03 - 1.87 (m, 1H), 0.97 - 0.88 (m, 18H), 0.77-0.68 (m, 3H).

[0673] Preparation 58. te / 7-Butyl 3-(6-Chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P58. OMOM To a solution of 6-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-ol (P57, 400 mg, 90% purity, 0.49 mmol) and DIPEA (126 mg, 0.98 mmol), in ACN (5 mb) was added PyBOP (380 mg, 0.74 mmol) at 25°C. The reaction mixture was stirred for 1 h at 25°C, then / c77-butyl 1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Pl, 220 mg, 90% purity, 0.73 mmol) was added. The resulted mixture was stirred for 16 h at 90°C and cooled to 0°C. The formed precipitate was filtered off and washed with cold ACN to afford the title compound P58 (135 mg, 90% purity, 25% yield) as a yellow solid. LCMS: Rt = 1.719 min; (ESI) calc, for C52H63ClF5N5O5Si [M+H]+ 996.4, found 996.3. JH NMR (400 MHz, CDCh), 5: 7.82 - 7.77 (m, 1H), 7.69 (s, 1H), 7.52 (s, 1H), 7.31 - 7.28 (m, 1H), 7.12 (s, 1H), 5.32 - 5.14 (m, 4H), 4.71 - 3.74 (m, 6H), 3.53 - 3.00 (m, 8H), 2.22 - 1.94 (m, 8H), 1.62 -1.54 (m, 12H), 0.91 - 0.82 (m, 18H), 0.58 - 0.50 (m, 3H).

[0674] Preparation 59. 2-(tert-Butyl) 7a-methyl (2S,3R,6R,7aS)-6-hydroxy-3- phenyltetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate P59. A mixture of methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (10.0 g, 55.06 mmol), benzaldehyde (5.60 mL, 55.06 mmol), tert-butyl acrylate (8.07 mL, 55.06 mmol) and TEA (9.18 mL, 66.07 mmol) in toluene (100 mL) was stirred at 120°C for 16 h and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography with a mixture of EtOAc and hexanes (20 to 50%) to afford the title compound P59 (9.0 g, 90% purity by rH NMR, 41% yield) as a white solid. LCMS: Rt = 1.174 min; (ESI) calc, for C20H27NO5 [M+H]+ 362.2, found 362.2. ’H NMR (400 MHz, CDCI3), 8: 7.33 - 7.23 (m, 5H), 4.66 - 4.64 (m, 2H), 3.84 - 3.79 (m, 1H), 3.74 (s, 3H), 2.98 - 2.94 (m, 1H), 2.75 - 2.69 (m, 1H), 2.52 - 2.46 (m, 3H), 1.87 - 1.82 (m, 1H), 1.64 - 1.63 (m, 1H), 0.99 (s, 9H).

[0675] Preparation 60. 2-(tert-Butyl) 7a-methyl (2S,3R,6S,7aS)-6-fluoro-3- phenyltetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate P60. To a solution of 2-(tert-butyl) 7a-methyl (2S,3R,6R,7aS)-6-hydroxy-3-phenyltetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate (P59, 4.0 g, 90% purity, 9.96 mmol) in THF (40 mL) was added BAST (9.18 mL, 49.80 mmol) at 0°C. The reaction mixture was stirred at 25°C for 3 h, diluted with water (40 mL), and extracted with EtOAc (3x20 mL). The combined organic layers were dried over anh. Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a mixture of EtOAc and hexanes (20 to 50%) to afford the title compound P60 (1.4 g, 90% purity by 1H NMR, 35% yield) as a yellow oil. LCMS: Rt= 1.524 min; (ESI) calc, for C20H26FNO4 [M+H]+ 364.2, found 364.2. ‘HNMR (400 MHz, CDCI3), 8: 7.33 - 7.28 (m, 3H), 7.15 - 7.13 (m, 2H), 5.24 - 5.10 (m, 1H), 4.83 (s, 1H), 3.91 - 3.84 (m, 1H), 3.79 (s, 3H), 3.07 - 2.82 (m, 3H), 2.49 - 2.47 (m, 2H), 2.09 - 1.95 (m, 1H), 0.99 (s, 9H).

[0676] Preparation 61. (2S,3R,6S,7aS)-6-fluoro-7a-(methoxycarbonyl)-3-phenylhexahydro-lH-pyrrolizine-2-carboxylic acid P61. A mixture of 2-( / e;7-butyl) 7a-methyl (2S,3R,6S,7aS)-6-fluoro-3-phenyltetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate (P60, 1.4 g, 90% purity, 3.47 mmol) in 6 M aq. solution of HC1 (10 mL) was stirred at 25°C for 16 h, with sat aq. solution of Na2COs to pH=5, extracted with EtOAc (3x10 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound P61 (1.0 g, 66% purity by LCMS, 62% yield) as a colorless oil. LCMS: Rt = 0.939 min; (ESI) calc, for Ci6Hi8FNO4[M+H]+ 308.1, found 308.1.

[0677] Preparation 62. Methyl (2S,3R,6S,7aS)-6-fluoro-2-(hydroxymethyl)-3-phenyltetrahydro-lH-pyrrolizine-7a(5H)-carboxylate P62. To a solution of (2S,3R,6S,7aS)-6-fluoro-7a-(methoxycarbonyl)-3-phenylhexahydro-lH-pyrrolizine-2-carboxylic acid (P61, 1.0 g, 66% purity, 2.15 mmol) in THF (10 mL) was added 1 M BH3 in THF (5 mL) at 0°C. The reaction mixture was stirred at 25°C for 1 h, quenched with EtOH (10 mL) and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a mixture of EtOAc and hexanes (20 to 50%) to afford the title compound P62 (520 mg, 90% purity by H NMR, 74% yield) as a colorless oil. LCMS: Rt = 0.783 min; (ESI) calc, for C16H20FNO3 [M+H]+ 294.1, found 294.1.1HNMR(400 MHz, CDCI3), 8: 7.39 - 7.33 (m, 3H), 7.13 - 7.11 (m, 2H), 5.35 - 5.22 (m, 1H), 4.79 - 4.77 (m, 1H), 3.81 (s, 3H), 3.30 - 2.92 (m, 6H), 2.48 - 2.45 (m, 1H), 2.15 -1.97 (m, 2H).

[0678] Preparation 63. Methyl (2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3- phenyltetrahydro-lH-pyrrolizine-7a(5H)-carboxylate P63. To a solution of methyl (2S,3R,6S,7aS)-6-fluoro-2-(hydroxymethyl)-3-phenyltetrahydro-lH-pyrrolizine-7a(5H)-carboxylate (P62, 400 mg, 90% purity, 1.23 mmol) and CsF (932 mg, 6.14 mmol) in DCM (4 mL) was added DAST (0.8 mL, 6.14 mmol) at 0°C. The reaction mixture was stirred at 25°C for 2 h, quenched with H2O (20 mL), and extracted with EtOAc (3x10 mL). The combined organic layers were dried over anh. Na2SO4, fdtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography with a mixture of EtOAc and hexanes (10 to 50%) to afford the title compound P63 (200 mg, 90% purity by H NMR, 50% yield) as a white solid. LCMS: Rt = 1.161 min; (ESI) calc, for C16H19F2NO2 [M+H]+ 296.1, found 296.1. rH NMR (400 MHz, CDCI3), 8: 7.38 - 7.32 (m, 3H), 7.08 - 7.07 (m, 2H), 5.30 (d, J= 53.6 Hz, 1H), 4.75 (s, 1H), 4.13 - 3.91 (m, 2H), 3.82 (s, 3H), 3.41 - 3.31 (m, 1H), 3.15 - 2.93 (m, 3H), 2.49 - 2.45 (m, 1H), 2.14- 1.93 (m, 2H).

[0679] Preparation 64 ((2S,3R,6S,7aS)-6-Fluoro-2-(fluoromethyl)-3-phenyltetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol P64. A mixture of methyl (2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-phenyltetrahydro-lH-pyrrolizine-7a(5H)-carboxylate (P63, 200 mg, 90% purity, 0.609 mmol), NaBH4 (60 mg, 1.52 mmol) and THF (20 mL) was stirred at 25°C for 12 h, quenched with MeOH (10 mL), poured into water (20 mL), and extracted with EtOAc (3x10 mL). The combined organic layers were dried over anh. Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography with a mixture of EtOAc and hexanes (20 to 50%) to afford the title compound P64 (150 mg, 90% purity by 'H NMR, 83% yield) as a white solid. LCMS: Rt = 0.995 min; (ESI) calc, for C15H19F2NO [M+H]+ 268.1, found 268.1. ‘HNMR (400 MHz, CDCI3), 8: 7.37 - 7.29 (m, 3H), 7.09 - 7.07 (m, 2H), 5.28 - 5.12 (m, 1H), 4.52 - 4.51 (m, 1H), 4.13 - 3.97 (m, 2H), 3.64 - 3.61 (m, 1H), 3.50 (d, J = 10.4 Hz, 1H), 3.41 - 3.30 (m, 1H), 3.15 - 2.94 (m, 2H), 2.34 - 2.24 (m, 2H), 2.13 - 1.99 (m, 1H), 1.77 (t,J = 12.8 Hz, 1H).

[0680] Preparation 65. tert-Butyl 3-(7-chloro-8-fluoro-2-(((2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-phenyltetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P65. To a solution of ((2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-phenyltetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (P64, 150 mg, 90% purity, 0.505 mmol) in THF (5 mL) was added NaH (40 mg, 60% in mineral oil, 1.01 mmol) at 0°C. The mixture was stirred for 30 min, and then / c / 'Z-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l- (2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P13, 278 mg, 90% purity, 0.510 mmol) was added. The resulted mixture was stirred at 25°C for 2 h, quenched with H2O (10 mL), and extracted with EtOAc (3x10 mL). The combined organic layers were dried over anh. Na?SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a mixture of EtOAc and hexanes (10 to 50%) to afford the title compound P65 (270 mg, 90% purity by LCMS, 67% yield) as yellow solid. LCMS: Rt = 1.394 min; (ESI) calc, for C35H38CIF5N6O3 [M+H]+ 721.3, found 721.2.

[0681] Preparation 66. terZ-Butyl 1-(2,2-difluorovinyl)-3-(8-fluoro-2-(((2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-phenyltetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate P66. A degassed mixture of tert-butyl 3-(7-chloro-8-fluoro-2-(((2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-phenyltetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P65, 270 mg, 90% purity, 0.337 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (345 mg, 0.674 mmol), K3PO4 (215 mg, 1.01 mmol), cataCXium A-Pd G3 (100 mg, 0.064 mmol) in dioxane (10 mb) and H2O (2 mb) was stirred at 100°C for 5 h in inert atm, diluted with water (10 mL), and extracted with EtOAc (3x10 mL). The combined organic layers were dried over anh. Na?SO4, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a mixture of EtOAc and hexanes (10 to 50%) to afford the title compound P66 (290 mg, 90% purity by HPLC, 72% yield) that was used directly for the next step.

[0682] Preparation 67. 4-(4-(1-(2,2-Difluorovinyl)-3,8-diazabicyclo[3.2. l]octan-3-yl)-8-fluoro-2-(((2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-phenyltetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((trii sopropyl silyl)ethynyl)naphthalen-2-ol P67. To a stirred solution of tert-butyl l-(2,2-difluorovinyl)-3-(8-fluoro-2-(((2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-phenyltetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P66, 290 mg, 90% purity, 0.244 mmol) in DCM (5 mL) at 0°C was added 4 M solution of HC1 in dioxane (5 mL) slowly. The reaction mixture was stirred at 0°C for 1 h and concentrated under pressure without heating to afford the title compound P67 (200 mg, 70% purity by LCMS, 62% yield) as yellow solid. The crude product was used directly for the next step. LCMS: Rt = 1.360 min; (ESI) calc, for C5iH56F6N6O2Si [M+H]+ 927.4 found 927.3.

[0683] Preparation 68. 2-(ter / -Butyl) 7a-methyl (2S,3R,6R,7aS)-6-hydroxy-3-(thiophen-3-yl)tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate P68. A mixture of methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (10.0 g, 55.06 mmol), thiophene-3-carbaldehyde (4.82 mL, 55.06 mmol), / c / 7-butyl acrylate (8.07 mL, 55.06 mmol) and TEA (9.18 mL, 66.07 mmol) in toluene (100 mL) was stirred at 120°C for 16 h and then concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with a mixture of hexanes and EtOAc (20 to 50%) to afford the title compound P68 (11.6 g, 90% purity by 'H NMR, 52% yield) as a white solid. LCMS: Rt= 1.091 min; (ESI) calc, for C18H25NO5S [M+H]+ 368.2, found 368.1. XH NMR (400 MHz, CDCI3), 8: 7.28 - 7.27 (m, 1H), 7.15 (s, 1H), 6.99 (d, J = 4.8 Hz, 1H), 4.82 (d, J= 8.8 Hz, Ih), 4.62 - 4.59 (m, 1H), 3.74 - 3.68 (m, 4H), 3.05 - 3.00 (m, 1H), 2.69 - 2.65 (m, IH), 2.58 - 2.40 (m, 3H), 1.84 - 1.79 (m, 2H), 1.09 (s, 9H).

[0684] Preparation 69. 2-(terLButyl) 7a-methyl (2S,3R,6S,7aS)-6-fluoro-3-(thiophen-3- yl)tetrahydro-lH-pyrrolizine-2,7a(5H)-di carboxylate P69. Bis-(2-methoxyethyl)aminosulfurtrif!uoride (11.29 mL, 61.23 mmol) was added at 0°C to a solution of 2-( / er / -butyl) 7a-methyl (2S,3R,6R,7aS)-6-hydroxy-3-(thiophen-3-yl)tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate (P68, 5.0 g, 90% purity, 12.25 mmol) in DCM (40 mL). The mixture was stirred at 25°C for 3 h, diluted with ice water (40 mL), and extracted with EtOAc (3x20 mL). The combined organic layers were dried over anh. Na2SO4, fdtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with a mixture of hexanes and EtOAc (10 to 20%) to afford the title compound P69 (2.2 g, 90% purity by 1H NMR, 44% yield) as yellow oil. LCMS: Rt= 1.184 min; (ESI) calc, for C18H24FNO4S [M+H]+ 370.1, found 370.1. 'H NMR (400 MHz, CDCh), 5: 7.29 - 7.28 (m, 1H), 7.11 (s, 1H), 6.87 (d, 7=4.4 Hz, 1H), 5.19 - 5.05 (m, 1H), 4.89 (d, J= 8.4 Hz, 1H), 3.82 - 3.77 (m, 4H), 3.09 - 2.79 (m, 3H), 2.47 - 2.43 (m, 2H), 2.01 - 1.87 (m, 1H), 1.09 (s, 9H).

[0685] Preparation 70. (2S,3R,6S,7aS)-6-Fluoro-7a-(methoxycarbonyl)-3-(thiophen-3-yl)hexahydro-lH-pyrrolizine-2-carboxylic acid P70. A solution of 2-(terM>utyl) 7a-methyl (2S,3R,6S,7aS)-6-fluoro-3-(thiophen-3-yl)tetrahydro-lH-pyrrolizine-2,7a(5H)-dicarboxylate (P69, 2.2 g, 90% purity, 5.36 mmol) in 6 M HC1 (10 mL) was stirred at 25°C for 16 h. After completion, the reaction was basified with Na2CO3 until pH=5. The solution was extracted with EtOAc (10 mL) three times. The combined organic layers were dried with anh. Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound P70 (1.1 g, 90% purity by ’H NMR, 59% yield) as colorless oil. LCMS: Rt= 0.508 min; (ESI) calc, for C14H16FNO4S [M+H]’ 314.1, found 314.0. 'H NMR (400 MHz, CDCh), 5: 7.29 - 7.28 (m, 1H), 7.14-7.13 (m, 1H), 6.87 (d, 7= 4.8 Hz, 1H), 5.19-5.06 (m, 1H), 4.98 (d, J= 7.6 Hz, 1H), 3.89 - 3.82 (m, 1H), 3.78 (s, 3H), 3.14 - 2.89 (m, 3H), 2.56 - 2.43 (m, 2H), 2.06 - 1.92 (m, 1H).

[0686] Preparation 71. Methyl (2S,3R,6S,7aS)-6-fluoro-2-(hydroxymethyl)-3-(thiophen-3-yl)tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate P71. To a solution of (2S,3R,6S,7aS)-6-fluoro-7a-(methoxycarbonyl)-3-(thiophen-3-yl)hexahydro-lH-pyrrolizine-2-carboxylic acid (1.1 g, 90% purity, 3.16 mmol) in THF (5 mL) was add 1 M BH3 in THF (5 mL) at 0°C. After stirred at 25°C for 1 h, the reaction was quenched with EtOH (10 mL) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (with a mixture of hexanes and EtOAc (20 to 50%) to afford the title compound P71 (810 mg, 90% purity by HNMR, 77% yield) as colorless oil. LCMS: Rt = 0.433 min; (ESI) calc, for C14H18FNO3S [M+H]+ 300.1, found 300.1.

[0687] Preparation 72. Methyl (2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-(thiophen-3-yl)tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate P72. To a solution of methyl (2S,3R,6S,7aS)-6-fluoro-2-(hydroxymethyl)-3-(thiophen-3-yl)tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate P71 (810 mg, 90% purity, 2.44 mmol) and CsF (1.85 g, 12.18 mmol) in DCM (10 mL) was added DAST (1.6 mL, 12.18 mmol) at 0°C. After stirred at 25°C for 2 h, the reaction was quenched with H2O (20 mL) and extracted with EtOAc (10 mL) three times. The combined organic layers were dried with anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with a mixture of hexanes and EtOAc (5 to 50%) to afford the title compound P72 (410 mg, 90% purity by H NMR, 50% yield) as a white solid. LCMS: Rt - 0.836 min; (ESI) calc, for C14H17F2NO2S [M+H]+ 302.1, found 302.0. ' H NMR (400 MHz, CDC13), 8: 7.36 - 7.34 (m, 1H), 7.06 (m, 1H), 6.79 (d, J= 4.4 Hz, 1H), 5.29 - 5.16 (m, 1H), 4.79 (d, J= 7.6 Hz, 1H), 4.19 - 3.98 (m, 2H), 3.79 (s, 3H), 3.34 - 3.23 (m, 1H), 3.14 - 2.91 (m, 3H), 2.49 - 2.44 (m, 1H), 2.04 - 1.89 (m, 2H).

[0688] Preparation 73. ((2S,3R,6S,7aS)-6-Fluoro-2-(fluoromethyl)-3-(thiophen-3-yl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)m ethanol P73. A mixture of methyl (2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-(thiophen-3-yl)tetrahydro-lH-pyrrolizine-7a(5H)-carboxylate (P72, 410 mg, 90% purity, 1.22 mmol), NaBH4 (116 mg, 3.06 mmol), and THF (20 mL) was stirred at 25°C for 12 h, quenched with MeOH (10 mL), poured into water (20 mL), and extracted with EtOAc (3x10 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with a mixture of hexanes and EtOAc (4:1) to afford the title compound P73 (310 mg, 66% purity by LCMS, 61% yield) as a white solid. LCMS: Rt= 0.593 min; (ESI) calc, for C13H17F2NOS [M+H]’ 274.1, found 274.0.

[0689] Preparation 74. te / 7-Butyl 3-(7-chloro-8-fluoro-2-(((2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-(thiophen-3-yl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate P74. To a solution of ((2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-(thiophen-3-yl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (P73, 310 mg, 66% purity, 0.749 mmol) in THF (5 mL) was added NaH (60 mg, 60% in oil, 1.50 mmol) at 0°C. The mixture was stirred for 30 min and then tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (P13, 374 mg, 90% purity, 0.763 mmol) was added. The mixture was stirred at 25°C for 2 h, quenched with H2O (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with a mixture of hexanes and EtOAc (10 to 50%) to afford the title compound P74 (530 mg, 90% purity by LCMS, 88% yield) as a yellow solid. LCMS: Rt= 1.326 min; (ESI) calc, for C33H36CIF5N6O3S [M+H]+ 727.3, found 727.1. 'HNMR (400 MHz, CDCI3) 5 8.75 (s, 1H), 7.36 - 7.35 (m, 1H), 7.07 - 7.02 (m, 1H), 6.81 - 6.80 (m, 1H), 5.38 - 5.25 (m, 1H), 5.15 - 5.07 (m, 1H), 4....

Claims

1. A compound of Formul a (IV):RiH NR3R1(IV),or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:Q is selected from N, C-H, C-F, C-Cl, C-CHF2, and C-CF3;R1 is selected from H and halogen;R2 is selected fromR4R4 is selected from H, halogen and -CR9R10Rn;R3 is H, orR3 and R11 form a bond;R6 is selected from H, aryl, heterocyclyl, heteroaryl, wherein aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, Ci-Ce alkoxy;R7 is H, orR6 and R7 together with the atoms to which they are attached and any intervening atoms, form a 3-8 membered cycloalkyl or heterocycle;R8 is selected from H, halogen and Ci-Ce alkyl, wherein alkyl is optionally substituted with one or more substitutients independently selected from halogen, CN, OH;R9 is selected from H and halogen;R10 is selected from H and halogen;R11 is selected from H, orR11 and R5 form a bond.

2. The compound of claim 1, wherein:Q is selected from N, C-H, C-F, C-Cl, C-CHF2, and C-CF3;R1 is selected from H and halogen;3. The compound of claim 1, wherein the compound is of Formula (IV-H):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

4. The compound of claim 1, wherein the compound is of Formula (IV-A):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

5. The compound of claim 1, wherein the compound is of Formula (IV-B):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

6. The compound of claim 1, wherein the compound is of Formula (IV-C):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

7. The compound of claim 1, wherein the compound is of Formula (IV-D):(IV-D),or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

8. The compound of claim 1, wherein the compound is of Formula (IV-E):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

9. The compound of claim 1, wherein the compound is of Formula (IV*):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

10. The compound of claim 1, wherein the compound is of Formula (IV**):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

11. The compound of claim 1, wherein the compound is of Formula (IV-1):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

12. The compound of claim 11, wherein the compound is of Formula (IV-1*):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

13. The compound of claim 12, wherein the compound is of Formula (IV-1*1):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

14. The compound of claim 12, wherein compound is of Formula (IV-1*2):(IV-1*2),or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

15. The compound of claim 1, wherein the compound is of Formula (IV-2):(IV-2),or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

16. The compound of claim 1, wherein the compound is of Formula (IV-3):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

17. The compound of claim 1, wherein the compound is of Formula (IV-4):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

18. The compound of claim 1, wherein the compound is of Formula (IV-5):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

19. The compound of claim 1, wherein the compound is of Formula (IV-6):(IV-6),or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

20. The compound of claim 1, wherein the compound is of Formula (IV-7):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

21. The compound of claim 1, wherein the compound is of Formula (IV-8):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

22. The compound of any one of claims 2-21, wherein R1 is F, or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.

23. A compound selected from:IUPAC Name4-(4-(1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetr ahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol4-[4-[(lR,5R)-1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-olIUPAC Name6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine# Structure IUPAC Name 6 H      ZF N \                    f3c A 1 AAx \ /       F nh2 6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine b H .N^^^F L J F N N=^ N<A|^N hn L L L X / \ YXyU irx 2 LX J o 1                                     f 4-(1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-y l)methoxy )py ri do [4,3 -d]pyrimidine 7 H _ / F _Z F /      I Z A NH k X< 0 N      ll 'X O   F JU 4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2- [[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidineIUPAC Name4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2-[[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidine4-[( IS, 5 S)-1-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)pyrido[4,3-d]pyrimidine4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)pyrido[4,3-d]pyrimidine#11IUPAC Name4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-7-fluoro-l,3-benzothiazol-2-amine4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-7-fluoro-l,3-benzothiazol-2-amine2-amino-4-(4-( 1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrileIUPAC Name2-amino-4-[4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-7-fluoro-b enzothi ophene-3 -carbonitrile2-amino-4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-7-fluoro-b enzothi ophene-3 -carbonitrile2-amino-4-[4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl] methoxy ] py ri do [4,3 -d]pyrimidin-7-yl]benzothiophene-3-carbonitrile2-amino-4-[4- [(1R, 5R)-1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]benzothiophene-3-carbonitrile18IUPAC Name4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrile4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-methyl-5 -(trifluoromethyl)-1H-i ndazol e-3 - carb oni tril e4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1 ]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl]pyrido[4,3 -d]pyrimidine2021IUPAC Name4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]pyrido[4,3-d]pyrimidine4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethy ny 1 -6-fluoro-naphthalen-2-ol4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethy ny 1 -6-fluoro-naphthalen-2-olIUPAC Name24236-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine6-[4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine# Structure IUPAC Name 26 H       / F k_Z F \                    CF3 / \ Ji JL J. X ,F x J\ ° n        ii N      7                      ।        ' \ /              F nh2 6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine 27 H _ / F £__Z F I nO ' JU c / n-nh 4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2- [[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazoline 28 H      zF xNx / ^\ Sk__Z F I NO ' JU n-nh 4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2- [[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolineStructureIUPAC Name29304-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)quinazoline4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)quinazoline4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-1,3 -b enzothi azol -2-amineIUPAC Name4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fl uoro-1,3 -b enzothi azol -2-amine2-amino-4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile2-amino-4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile2-amino-4-[4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile#3637IUPAC Name2-amino-4-[4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrile4-[4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrile3940IUPAC Name4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]quinazoline4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(tri fluoromethyl)-1H-indazol-4-yl]quinazoline4-(6-Chloro-4-( 1-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol42IUPAC Name4-[6-chloro-4-[(l S,5S)-1-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethy ny 1 -6-fluoro-naphthalen-2-ol4-[6-chloro-4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethy ny 1 -6-fluoro-naphthalen-2-ol6-[6-chloro-4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amineStructureIUPAC Name456-[6-chloro-4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine6-[6-chloro-4-[(l S,5S)-1-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine6-[6-chloro-4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1 ]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amineStructureIUPAC Name47486-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2-[[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazoline6-chloro-4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2-[[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazoline6-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)quinazoline5052StructureIUPAC Name6-chloro-4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)quinazoline4-[6-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-1,3 -b enzothi azol -2-amine4-[6-chloro-4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-1,3 -b enzothi azol -2-amineIUPAC Name2-amino-4-[6-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile2-amino-4- [6-chloro-4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile2-amino-4-[6-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile2-amino-4- [6-chloro-4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile58IUPAC Name4-[6-chloro-4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazol e-3 - carb onitril e4-[6-chloro-4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-1H-indazole-3-carbonitrile6-chloro-4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]quinazolineStructureIUPAC Name606-chl oro-4- [(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]quinazoline4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethynyl -6-fluoro-naphthalen-2-ol624-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-5 -ethynyl -6-fluoro-naphthalen-2-olIUPAC Name63646-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine6-[4-[(lR,5R)-1-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine# Structure IUPAC Name 66 H       / F _Z F F, 6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine x                      । ^...      M     MM_ x >x o n       Y O J JU '—f        f3X y F 67 H Nx \    nA n / F F ^YF rN L JL JL NH TXJ 4-[(lS,5S)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-6,8 -difluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazoline 68 H _ Z zNV\ Ik__Z F i O F JU C / n-nh 4-[(lR,5R)-l-(2,2- difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-6,8-difluoro-2- [[(2R, 8 S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolineStructureIUPAC Name704-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)quinazoline4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)quinazoline4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-1,3 -b enzothi azol -2-amineIUPAC Name4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fl uoro-1,3 -b enzothi azol -2-amine2-amino-4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile2-amino-4-[4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile2-amino-4-[4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile#7677IUPAC Name2-amino-4-[4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]benzothiophene-3-carbonitrile4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrile4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrileStructureIUPAC Name4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]quinazoline804-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6,8-difluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]quinazoline4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-olIUPAC Name834-[4-[(lR,5R)-1-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine# Structure IUPAC Name 85 H       / F £__Z F F          xX     / CF3 \       n /       JL <X JI ,NH2 O F JU '---'              F3c y F 6-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1 ]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine 86 H      ZF N F       X. / ^ / CF3 Y      n ^y /       xX          / N. ,NH2 VX NuXJ --          F3c Y F 6-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-4-fluoro-5-(trifluoromethyl)pyridin-2-amine 87 H       / F __Z F F          xX     / CF3 Y          N             1 N^ryXz NO JU / n-nh 4-[(lS,5S)-l-(2,2- difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2- [[(2R, 8 S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolineIUPAC Name4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazoline894-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-6-(trifluoromethyl)quinazoline4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-6-(trifluoromethyl)quinazolineIUPAC Name4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-7-fluoro-l,3-b enzothi azol -2 -ami ne4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-7-fluoro-l,3-b enzothi azol -2 -ami ne2-amino-4-[4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-7-fluoro-b enzothi ophene-3 -carbonitrileIUPAC Name2-amino-4-[4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-7-fluoro-b enzothi ophene-3 -carbonitrile2-amino-4-[4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7 -y 1 ]b enzothi ophene-3 -carbonitrile2-amino-4-[4-[(lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]benzothiophene-3-carbonitrile9798IUPAC Name4-[4-[(lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrile4-[4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-6-methyl-5-(trifluoromethyl)-lH-indazole-3-carbonitrile4-[(lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]-6-(trifluoromethyl)quinazolineIUPAC Name4-[(lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl]-6-(trifluoromethyl)quinazoline4-(2-(((S)-2-(Difluoromethylene)tetrahyd ro-1 H-py rrolizin-7 a(5H)-yl)methoxy)-4-(l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol4-(2-(((S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy )-4-(( 1R, 5R)-1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-olIUPAC Name4-(2-(((S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthal en -2-ol4-(2-(((R)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy )-4-( 1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol4-(2-(((R)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-y 1)- 8 -fluoropy ri do [4,3 -d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-olIUPAC Name4-(2-(((R)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthal en -2-ol4-(4-(1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3 -yl)-8-fluoro-2-((6'-methylenetetrahydrospirofcy clopropane-1,3 '-pyrrolizin] -7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol2-amino-4-(6-(difluoromethyl)-4-( 1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrileIUPAC Name2-amino-4-(6-chloro-4-( 1 -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile(S)-2-amino-4-(6-chloro-4-((lR,5R)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile(S)-2-amino-4-(6-chloro-4-((1 S,5S)-l-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile(R)-2-amino-4-(6-chloro-4-((lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile# Structure IUPAC Name 113 H        ZF N            N NH2 / \ k k 1     / \ O Ml (R)-2-amino-4-(6-chloro-4-((lS,5S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorob enzo [b ] thi ophene-3-carbonitrile 114 H       ZF N N__A f F             N F—d       U\z^x / C| m kM      A /        ks. J<5x k     k / NH2 \ xov y\ ZM N >        O / \__ /          f <7 ys F 2-amino-4-(6-chloro-2-(((S)-2- (difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 115 H        / F r>____<g f F             N f~4     N^yv01 \\\ X / X 0          .., / M n x                         / \__ /          f < / ys F (R)-2-amino-4-(6-chloro-2-«(S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy )-4-(( 1S,5S)-1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrileIUPAC Name(S)-2-amino-4-(6-chloro-2-(((S)-2-(difluoromethylene)tetrahydr o- lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((lS,5S)-l-(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl )-8-fluoroquinazolin-7-yl )-7-fluorobenzo[b]thiophene-3-carbonitrile(R)-2-amino-4-(6-chloro-2-(((S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(( 1R, 5R)-1 -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-7-fluorob enzo [b ] thi ophene-3-carbonitrile(S)-2-amino-4-(6-chloro-2-(((S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(( 1R, 5R)-1 -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile2-amino-4-(4-( 1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile# Structure IUPAC Name 120 H        zF K__Z f F /     Ax Ax A A / NH2 \ X o ^N   X^^X^ \____y          f Z ys F (R)-2-amino-4-(4-((lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 121 H        zF on N          F P        1     AFn /     A> Ax A A / Nh2 \   O    Y^X ZX< \___ /              F <7 F (R)-2-amino-4-(4-(( 1S, 5 S)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 122 H        zF ,N x / ^X K__Z f F f         1     AFn / \^x A> Ax A A / Nh2 \    o n    X Zx^ N >               1      / / "'"€ 1 \ /          F ( / V-S F (S)-2-amino-4-(4-((lR,5R)-l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile123IUPAC Name(S)-2-amino-4-(4-((l S, 5 S)-1 -(2,2-difluoroviny 1)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile1244-(4-(1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,3R,6S,7aS)-6-fluoro-2-(fluorom ethyl )-3-phenyltetrahy dro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol1254-(4-(1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6’5*,7a’7?*)-6'-fluorotetrahydrospiro[cyclop ropane-1,3 '-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol126127128StructureIUPAC Name4-(4-(1 -(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,3R,6S,7aS)-6-fluoro-2-(fluoromethyl)-3-(thiophen-3 -yl)tetrahydro-1H-pyrrolizin-7a(5H)-y l)methoxy )py ri do [4,3 -d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol4-(2-(((2S,3R,6S,7aS)-3-(2,2-Difluorobenzo[d][l,3]dioxol-5-yl)-6-fluoro-2-(fluoromethyl)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol2-amino-4-(6-chloro-2-(((R)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(l-(2,2-difluorovinyl )-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-7-fluorob enzo [b ] thi ophene-3-carbonitrile129130IUPAC Name2-amino-4-(2-(((S)-2-(difluoromethylene)tetrahydr o-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(l-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile4-(2-((6'-(difluoromethylene)tetrahydr ospiro[cyclopropane-l,3'-pyrrolizin]-7a'(5'H)-yl)methoxy)-4-( 1-(2,2-difluorovinyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-olor a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

24. A pharmaceutical composition comprising the compound of any one of claims 123 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.

25. The pharmaceutical composition of claim 24, further comprising one or more additional pharmaceutically active agents.

26. A method of inhibiting of KRAS(G12D) in a cell, comprising contacting the cell with a compound of any one of claims 1-23 or a pharmaceutical composition of claim 24 or 25.

27. The method of claim 26, wherein the contacting is in vitro or in vivo.

28. A method for the treatment or prevention of a disease or disorder associated with KRAS(G12D) comprising administering to a subject in need thereof a compound of any one of claims 1-23 or a pharmaceutical composition of claim 24 or 25.

29. The method of claim 28, wherein the disease or disorder is selected from the group consisting of Lung Cancer (LNCR); Pancreatic Cancer (PNCA); Colorectal Cancer (CRC); Adenocarcinoma; Gastric Cancer (GASC); Breast Cancer (BC); Noonan Syndrome 1 (NSl); Lung Cancer Susceptibility 3 (LNCR3); Ovarian Cancer (OC); Juvenile Myelomonocytic Leukemia (JMML); Leukemia, Acute Myeloid (AML); Cardiofaciocutaneous Syndrome 1 (CFC1); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Myeloma, Multiple (MM); Leukemia, Chronic Myeloid (CML); Lynch Syndrome (HNPCC); Hepatocellular Carcinoma (HCC); Melanoma; Prostate Cancer (PC); Esophageal Cancer (ESCR); Familial Adenomatous Polyposis (FAP); Costello Syndrome (CSTLO); Skin Melanoma; Gastrointestinal Stromal Tumor (GIST); Tatton-Brown-Rahman Syndrome (TBRS); Mismatch Repair Cancer Syndrome 1 (MMRCS1); Glioma Susceptibility 1 (GLM1); Retinoblastoma (RBI); Brain Cancer; Squamous Cell Carcinoma, Head and Neck (HNSCC); Down Syndrome; Tuberous Sclerosis 1 (TSC1); Deficiency Anemia; Multiple Endocrine Neoplasia, Type I (MEN1); Medulloblastoma (MDB); Hypertension, Essential (EHT); Fanconi Anemia, Complementation Group a (FANCA); Type 2 Diabetes Mellitus (T2D); Amyotrophic Lateral Sclerosis 1 (ALS1).

30. The method of claim 29, wherein the disease or disorder is Lung Cancer (LNCR).

31. The method of claim 29, wherein the disease or disorder is Pancreatic Cancer (PNCA)32. The method of claim 29, wherein the disease or disorder is Colorectal Cancer (CRC).

33. The method of any one of claims 26-32, wherein the subject is a mammal.

34. The method of claim 33, wherein the subject is a human.